4,975 results on '"DRUG development"'
Search Results
2. The Role of Furin and Its Therapeutic Potential in Cardiovascular Disease Risk.
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Fry, Hannah, Mazidi, Mohsen, Kartsonaki, Christiana, Clarke, Robert, Walters, Robin G., Chen, Zhengming, and Millwood, Iona Y.
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EAST Asians , *PROTEOLYTIC enzymes , *DRUG target , *DRUG development , *GENETIC variation - Abstract
Furin is an important proteolytic enzyme, converting several proteins from inactive precursors to their active forms. Recently, proteo-genomic analyses in European and East Asian populations suggested a causal association of furin with ischaemic heart disease, and there is growing interest in its role in cardiovascular disease (CVD) aetiology. In this narrative review, we present a critical appraisal of evidence from population studies to assess furin's role in CVD risk and potential as a drug target for CVD. Whilst most observational studies report positive associations between furin expression and CVD risk, some studies report opposing effects, which may reflect the complex biological roles of furin and its substrates. Genetic variation in FURIN is also associated with CVD and its risk factors. We found no evidence of current clinical development of furin as a drug target for CVD, although several phase 1 and 2 clinical trials of furin inhibitors as a type of cancer immunotherapy have been completed. The growing field of proteo-genomics in large-scale population studies may inform the future development of furin and other potential drug targets to improve the treatment and prevention of CVD. [ABSTRACT FROM AUTHOR]
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- 2024
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3. In Silico Screening of Therapeutic Targets as a Tool to Optimize the Development of Drugs and Nutraceuticals in the Treatment of Diabetes mellitus : A Systematic Review.
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Gomes, Ana Francisca T., de Medeiros, Wendjilla F., Medeiros, Isaiane, Piuvezam, Grasiela, da Silva-Maia, Juliana Kelly, Bezerra, Ingrid Wilza L., and Morais, Ana Heloneida de A.
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DRUG development , *MOLECULAR dynamics , *DRUG target , *DESIGNER drugs , *MOLECULAR docking - Abstract
The Target-Based Virtual Screening approach is widely employed in drug development, with docking or molecular dynamics techniques commonly utilized for this purpose. This systematic review (SR) aimed to identify in silico therapeutic targets for treating Diabetes mellitus (DM) and answer the question: What therapeutic targets have been used in in silico analyses for the treatment of DM? The SR was developed following the guidelines of the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis, in accordance with the protocol registered in PROSPERO (CRD42022353808). Studies that met the PECo strategy (Problem, Exposure, Context) were included using the following databases: Medline (PubMed), Web of Science, Scopus, Embase, ScienceDirect, and Virtual Health Library. A total of 20 articles were included, which not only identified therapeutic targets in silico but also conducted in vivo analyses to validate the obtained results. The therapeutic targets most frequently indicated in in silico studies were GLUT4, DPP-IV, and PPARγ. In conclusion, a diversity of targets for the treatment of DM was verified through both in silico and in vivo reassessment. This contributes to the discovery of potential new allies for the treatment of DM. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Toxicological and Pharmacological Activities, and Potential Medical Applications, of Marine Algal Toxins.
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Gao, Xinyu, Wang, Hanyi, Chen, Kuilin, Guo, Yifan, Zhou, Jin, and Xie, Weidong
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ALGAL toxins , *BIOACTIVE compounds , *LIFE sciences , *DRUG development , *SCIENTIFIC community - Abstract
Marine algal toxins have garnered significant attention in the research community for their unique biochemical properties and potential medical applications. These bioactive compounds, produced by microalgae, pose significant risks due to their high toxicity, yet offer promising therapeutic benefits. Despite extensive research identifying over 300 marine algal toxins, including azaspiracids, brevetoxins, cyclic imines, and yessotoxins, gaps remain in the understanding of their pharmacological potential. In this paper, we critically review the classification, bioactive components, toxicology, pharmacological activities, and mechanisms of these toxins, with a particular focus on their clinical applications. Our motivation stems from the increasing interest in marine algal toxins as candidates for drug development, driven by their high specificity and affinity for various biological receptors. We aim to bridge the gap between toxicological research and therapeutic application, offering insights into the advantages and limitations of these compounds in comparison to other bioactive substances. This review not only enhances the understanding of marine algal toxins' complexity and diversity, but also highlights their extensive application potential in medicine and bioscience, providing a foundation for future research and development in this field. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition.
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Cavina, Lorenzo, Bouma, Mathijs J., Gironés, Daniel, and Feiters, Martin C.
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WEST Nile virus , *DENGUE viruses , *GLOBAL burden of disease , *ZIKA virus , *DRUG development - Abstract
Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, with a focus on NS2B-NS3 inhibition. We systematically examined clinical trials, preclinical efficacy studies, and modes of action for various viral replication inhibitors, emphasizing allosteric and orthosteric drugs inhibiting NS2B-NS3 protease with in vivo efficacy and in vitro-tested competitive NS2B-NS3 inhibitors with cellular efficacy. Our findings revealed that several compounds with in vivo preclinical efficacy failed to show clinical antiviral efficacy. NS3-NS4B inhibitors, such as JNJ-64281802 and EYU688, show promise, recently entering clinical trials, underscoring the importance of developing novel viral replication inhibitors targeting viral machinery. To date, the only NS2B-NS3 inhibitor that has undergone clinical trials is doxycycline, however, its mechanism of action and clinical efficacy as viral growth inhibitor require additional investigation. SYC-1307, an allosteric inhibitor, exhibits high in vivo efficacy, while temoporfin and methylene blue represent promising orthosteric non-competitive inhibitors. Compound 71, a competitive NS2B-NS3 inhibitor, emerges as a leading preclinical candidate due to its high cellular antiviral efficacy, minimal cytotoxicity, and favorable in vitro pharmacokinetic parameters. Challenges remain in developing competitive NS2B-NS3 inhibitors, including appropriate biochemical inhibition assays as well as the selectivity and conformational flexibility of the protease, complicating effective antiviral treatment design. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma.
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Britton, William R., Cioffi, Isabel, Stonebraker, Corinne, Spence, Matthew, Okolo, Ogoegbunam, Martin, Cecilia, Henick, Brian, Nakagawa, Hiroshi, and Parikh, Anuraag S.
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THERAPEUTIC use of antineoplastic agents , *SQUAMOUS cell carcinoma , *CLINICAL drug trials , *PROTEINS , *CANCER , *EPITHELIAL-mesenchymal transition , *CANCER invasiveness , *HEAD & neck cancer , *IMMUNOTHERAPY , *CELLULAR signal transduction , *METASTASIS , *CANCER chemotherapy , *FIBROBLASTS , *DRUG development , *CYTOKINES , *INDIVIDUALIZED medicine , *TRANSFORMING growth factors-beta , *NEOVASCULARIZATION , *DRUG resistance - Abstract
Simple Summary: TGF-β is an important cytokine shown to drive oncogenesis in head and neck squamous cell carcinoma (HNSCC) through its diverse influences on the tumor microenvironment. While this cytokine is vital in maintaining tissue homeostasis in normal head and neck epithelia, in cancer, it paradoxically drives metastasis, angiogenesis, immune evasion, and therapy resistance. Despite promising preclinical data, the outcome of clinical trials of TGF-β inhibitors for HNSCC has been suboptimal. Patient stratification is warranted to improve this targeted therapy. Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Developmental Therapeutics in Metastatic Prostate Cancer: New Targets and New Strategies.
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Zhang, Jingsong and Chadha, Juskaran S.
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THERAPEUTIC use of immunoglobulins , *LIGANDS (Biochemistry) , *CLINICAL trials , *PROSTATE tumors , *CELLULAR therapy , *BLOOD coagulation factors , *PROSTATE-specific membrane antigen , *DRUG development , *TUMOR antigens , *MEMBRANE proteins , *CELL receptors - Abstract
Simple Summary: The developments of radioligand therapy, immunotherapy, and targeted chemotherapy have led to dozens of clinical trials targeting tumor-associated surface antigens in metastatic prostate cancer. Emerging clinical data on the development of these new therapies were summarized and discussed. There is an unmet need to develop new treatments for metastatic prostate cancer. With the development of targeted radioligand therapies, bispecific T cell engagers, antibody–drug conjugates and chimeric antigen receptor T cell (CAR T) therapies, tumor-associated cell surface antigens have emerged as new therapeutic targets in metastatic prostate cancer. Ongoing and completed clinical trials targeting prostate-specific membrane antigen (PSMA), six transmembrane epithelial antigens of the prostate 1 (STEAP1), kallikrein-related peptidase 2 (KLK2), prostate stem cell antigen (PSCA), and delta-like protein 3 (DLL3) in metastatic prostate cancer were reviewed. Strategies for sequential or combinational therapy were discussed. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Proceedings from the First Onco Summit: LATAM Chapter, 19–20 May 2023, Rio de Janeiro, Brazil.
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Hungria, Vania, Sureda, Anna, Campelo, Garcia Rosario, Salvino, Marco Aurélio, and Ramasamy, Karthik
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TREATMENT of lung tumors , *MULTIPLE myeloma treatment , *HODGKIN'S disease treatment , *INTERPROFESSIONAL relations , *CANCER patient medical care , *CLINICAL medicine research , *CONFERENCES & conventions , *ONCOLOGISTS , *DRUG development - Abstract
Simple Summary: The first Onco Summit: The Latin American (LATAM) Chapter was held from 19–20 May 2023, in Rio de Janeiro, Brazil. This educational initiative aimed to discuss the current challenges in cancer care, both globally and in LATAM, and foster the exchange of best practices to address these challenges. The Summit brought together more than 30 international and regional experts and more than 300 oncology specialists to deliberate on the advancements and barriers in oncology, with a focus on strategies tailored to the specific needs of LATAM. This report provides an overview of the key discussions among cancer specialists at the Summit. The Onco Summit 2023: The Latin American (LATAM) Chapter took place over two days, from 19–20 May 2023, in Brazil. The event aimed to share the latest updates across various oncology disciplines, address critical clinical challenges, and exchange best practices to ensure optimal patient treatment. More than 30 international and regional speakers and more than 300 oncology specialists participated in the Summit. The Summit discussions centered on common challenges and therapeutic advances in cancer care, with a specific focus on the unique obstacles faced in LATAM and examples of adaptable strategies to address these challenges. The Summit also facilitated the establishment of a network of oncologists, hematologists, and scientists in LATAM, enabling collaboration to improve cancer care, both in this region and globally, through drug development and clinical research. This report summarizes the key discussions from the Summit for the global and LATAM oncology community. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Synthesis and Antiallergic Activity of Dicoumarin Derivatives.
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Zhang, Yuying, Wang, Xiaoyu, and Zhou, Dejun
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CLIMATE extremes , *DRUG development , *MAST cells , *ANTIALLERGIC agents , *GREENHOUSE effect - Abstract
Allergies are one of the diseases whose incidence rates have increased in recent years due to the greenhouse effect and extreme climate change. Therefore, the development of new antiallergic drugs has attracted the interest of researchers in chemistry and pharmacy fields. Dicoumarin is a coumarin derivative with various biological activities, but its antiallergic activity has not been evaluated. In this study, 14 different dicoumarin derivatives were synthesized by diethylamine-catalyzed condensation reactions of 4-hydroxycoumarin with 14 different aldehydes, and they were identified on the basis of their spectral data. The dicoumarin derivatives were subjected to studies on the degranulation of rat basophilic leukemia cells (RBL-2H3 cells) and mouse bone-marrow-derived mast cells (mBMMCs), and some of them showed good inhibitory effects on the degranulation of the two types of mast cells, demonstrating their good antiallergic activity. This study presents a new method of developing new antiallergic drugs. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth.
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Novobrantseva, Tatiana, Manfra, Denise, Ritter, Jessica, Razlog, Maja, O'Nuallain, Brian, Zafari, Mohammad, Nowakowska, Dominika, Basinski, Sara, Phennicie, Ryan T., Nguyen, Phuong A., Brehm, Michael A., Sazinsky, Stephen, and Feldman, Igor
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RNA metabolism , *CLINICAL drug trials , *SMALL interfering RNA , *LIGANDS (Biochemistry) , *RESEARCH funding , *T cells , *MACROPHAGES , *ANTINEOPLASTIC agents , *INVESTIGATIONAL drugs , *CELL physiology , *IMMUNOTHERAPY , *IMMUNOGLOBULINS , *GLYCOPROTEINS , *MONOCLONAL antibodies , *CELL lines , *IMMUNE checkpoint inhibitors , *GENE expression , *DRUG efficacy , *DRUG development , *TUMORS , *INFLAMMATION , *BIOMARKERS , *SEQUENCE analysis , *PHARMACODYNAMICS - Abstract
Simple Summary: Cancer can create a shield of suppressive innate immune cells that stop our body's natural defenses from tumors. VTX-0811 is a new drug that targets these cells and turns them from allies of cancer to fighters against it. Preclinical tests show that it works in the lab on human cells and tumors and is safe and efficacious in animals. The results are promising and pave the way for human trials to see if VTX-0811 can become a new powerful weapon against cancer. Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance. [ABSTRACT FROM AUTHOR]
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- 2024
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11. mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes.
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Troise, Dario, Mercuri, Silvia, Infante, Barbara, Losappio, Vincenzo, Cirolla, Luciana, Netti, Giuseppe Stefano, Ranieri, Elena, and Stallone, Giovanni
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MTOR inhibitors , *CELL growth , *DRUG development , *MEDICAL care costs , *AGING - Abstract
The aging process contributes significantly to the onset of chronic diseases, which are the primary causes of global mortality, morbidity, and healthcare costs. Numerous studies have shown that the removal of senescent cells from tissues extends lifespan and reduces the occurrence of age-related diseases. Consequently, there is growing momentum in the development of drugs targeting these cells. Among them, mTOR and SGLT-2 inhibitors have garnered attention due to their diverse effects: mTOR inhibitors regulate cellular growth, metabolism, and immune responses, while SGLT-2 inhibitors regulate glucose reabsorption in the kidneys, resulting in various beneficial metabolic effects. Importantly, these drugs may act synergistically by influencing senescence processes and pathways. Although direct studies on the combined effects of mTOR inhibition and SGLT-2 inhibition on age-related processes are limited, this review aims to highlight the potential synergistic benefits of these drugs in targeting senescence. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Integrative Approaches in Non-Small Cell Lung Cancer Management: The Role of Radiotherapy.
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Visa, Maxime A., Abazeed, Mohamed E., and Avella Patino, Diego
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NON-small-cell lung carcinoma , *TUMOR classification , *DRUG development , *CHEMORADIOTHERAPY , *IMMUNOTHERAPY - Abstract
Treatment guidelines for non-small cell lung cancer (NSCLC) vary by several factors including pathological stage, patient candidacy, and goal of treatment. With many therapeutics and even more combinations available in the NSCLC clinician's toolkit, a multitude of questions remain unanswered vis-a-vis treatment optimization. While some studies have begun exploring the interplay among the many pillars of NSCLC treatment—surgical resection, radiotherapy, chemotherapy, and immunotherapy—the vast number of combinations and permutations of different therapy modalities in addition to the modulation of each constituent therapy leaves much to be desired in a field that is otherwise rapidly evolving. Given NSCLC's high incidence and lethality, the experimentation of synergistic benefits that combinatorial treatment may confer presents a ripe target for advancement and increased understanding without the cost and burden of novel drug development. This review introduces, synthesizes, and compares prominent NSCLC therapies, placing emphasis on the interplay among types of therapies and the synergistic benefits some combinatorial therapies have demonstrated over the past several years. [ABSTRACT FROM AUTHOR]
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- 2024
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13. An Evaluation of Sex-Specific Pharmacokinetics and Bioavailability of Kokusaginine: An In Vitro and In Vivo Investigation.
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Shang, Kaiqi, Ge, Chengyu, Zhang, Yindi, Xiao, Jing, Liu, Shao, and Jiang, Yueping
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LIVER microsomes , *DRUG metabolism , *DRUG development , *DRUG efficacy , *LIQUID chromatography - Abstract
Kokusaginine is a bioactive ingredient extracted from Ruta graveolens L., which has a range of biological activities. Its pharmacokinetic (PK) properties are particularly important for clinical applications; however, they have not been fully elucidated. In addition, the effect of sex differences on drug metabolism is increasingly being recognized, but most studies have ignored this important factor. This study aims to fill this knowledge gap by taking an in-depth look at the PK properties of kokusaginine and how gender affects its metabolism and distribution in the body. It also lays the foundation for clinical drug development. In this study, a sensitive ultra-high-performance liquid chromatography (UPLC) method was developed and validated for quantifying kokusaginine in Sprague Dawley (SD) rat plasma and tissue homogenates. Metabolic stability was evaluated in vitro using gender-specific liver microsomes. Innovatively, we incorporated sex as a variable into both in vitro and in vivo PK studies in SD rats, analyzing key parameters with Phoenix 8.3.5 software. The developed UPLC method demonstrated high sensitivity and precision, essential for PK analysis. Notably, in vitro studies revealed a pronounced sex-dependent metabolic variability (p < 0.05). In vivo, gender significantly affected the Area Under the Moment Curve (AUMC)(0-∞) of the plasma PK parameter (p < 0.05) and the AUMC(0-t) of brain tissue (p < 0.0001), underscoring the necessity of sex-specific PK assessments. The calculated absolute bioavailability of 71.13 ± 12.75% confirmed the favorable oral absorption of kokusaginine. Additionally, our innovative tissue-plasma partition coefficient (Kp) analysis highlighted a rapid and uniform tissue distribution pattern. This study presents a sex-inclusive PK evaluation of kokusaginine, offering novel insights into its metabolic profile and distribution. These findings are instrumental for informing clinical medication practices, dosage optimization, and a nuanced understanding of drug efficacy and safety in a sex-specific context. [ABSTRACT FROM AUTHOR]
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- 2024
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14. The Pivotal Role of Preclinical Animal Models in Anti-Cancer Drug Discovery and Personalized Cancer Therapy Strategies.
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Guo, Haochuan, Xu, Xinru, Zhang, Jiaxi, Du, Yajing, Yang, Xinbing, He, Zhiheng, Zhao, Linjie, Liang, Tingming, and Guo, Li
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DRUG discovery , *ANTINEOPLASTIC agents , *ANIMAL models in research , *MEDICAL research , *DRUG development - Abstract
The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Supercritical Fluids: An Innovative Strategy for Drug Development.
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Liu, Hui, Liang, Xiaoliu, Peng, Yisheng, Liu, Gang, and Cheng, Hongwei
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SUPERCRITICAL fluids , *DRUG development , *DRUG laws , *SUSTAINABLE development , *TREATMENT effectiveness , *DRUG delivery systems - Abstract
Nanotechnology plays a pivotal role in the biomedical field, especially in the synthesis and regulation of drug particle size. Reducing drug particles to the micron or nanometer scale can enhance bioavailability. Supercritical fluid technology, as a green drug development strategy, is expected to resolve the challenges of thermal degradation, uneven particle size, and organic solvent residue faced by traditional methods such as milling and crystallization. This paper provides an insight into the application of super-stable homogeneous intermix formulating technology (SHIFT) and super-table pure-nanomedicine formulation technology (SPFT) developed based on supercritical fluids for drug dispersion and micronization. These technologies significantly enhance the solubility and permeability of hydrophobic drugs by controlling the particle size and morphology, and the modified drugs show excellent therapeutic efficacy in the treatment of hepatocellular carcinoma, pathological scarring, and corneal neovascularization, and their performance and efficacy are highlighted when administered through multiple routes of administration. Overall, supercritical fluids have opened a green and efficient pathway for clinical drug development, which is expected to reduce side effects and enhance therapeutic efficacy. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review.
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Medina Pérez, Víctor Manuel, Baselga, Marta, and Schuhmacher, Alberto J.
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THERAPEUTIC use of monoclonal antibodies , *DRUG toxicity , *PATIENT safety , *RESEARCH funding , *IMMUNOGLOBULINS , *BLOOD-brain barrier , *SYSTEMATIC reviews , *MEDLINE , *DRUG efficacy , *DRUG stability , *MEDICAL databases , *TUMORS , *DRUG development , *ONLINE information services - Abstract
Simple Summary: Antibody–drug conjugates (ADCs) have emerged as a potent cancer therapy by selectively delivering cytotoxic payloads to tumors. However, they face limitations due to acquired resistance and adverse effects. New ADC formats, such as bispecific ADCs and probody–drug conjugates, offer potential solutions. Nevertheless, single-domain antibodies (VHHs), also known as nanobodies, present a promising alternative. VHHs possess unique characteristics over ADCs, including a smaller size, enhanced tissue penetration, and rapid clearance. Their stability, solubility, and manufacturability surpass those of conventional antibodies, enabling cost-effective production and expanding the range of targetable antigens. Therefore, VHHs can mitigate some of the risks associated with conventional ADCs, representing an exciting prospect for next-generation ADCs. Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs—such as their small size, enhanced tissue penetration, stability, and cost-effectiveness—make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Methods: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. Results: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood–brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH–drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. Conclusions: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Advancements in Research and Treatment Applications of Patient-Derived Tumor Organoids in Colorectal Cancer.
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van der Graaff, Denise, Seghers, Sofie, Vanclooster, Pieterjan, Deben, Christophe, Vandamme, Timon, and Prenen, Hans
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THERAPEUTIC use of antineoplastic agents , *CLINICAL drug trials , *TISSUES , *SURVIVAL rate , *GENOMICS , *DRUG resistance in cancer cells , *CELL physiology , *CANCER patient medical care , *ANTINEOPLASTIC agents , *COLORECTAL cancer , *CANCER patients , *CELL lines , *TRANSLATIONAL research , *GENES , *WORLD health , *MEDICAL research , *GENOME editing , *MEDICINE , *STEM cells , *DRUG development , *BIOMARKERS , *SEQUENCE analysis - Abstract
Simple Summary: Colorectal cancer (CRC) is a major global health issue, causing many deaths each year. The current treatments often face challenges due to the cancer's resistance to drugs, making it hard to treat effectively. This research focuses on using patient-derived tumor organoids (PDTOs), which are small, three-dimensional models grown from a patient's tumor, to better understand and predict how CRC responds to treatments. PDTOs mimic the actual tumor environment closely, making them more reliable than traditional models. By studying PDTOs, researchers hope to find new ways to use existing drugs, understand why resistance happens, and develop better treatment plans tailored to individual patients. This approach could lead to significant advancements in how CRC is managed, potentially improving survival rates and patient outcomes. Colorectal cancer (CRC) remains a significant health burden globally, being the second leading cause of cancer-related mortality. Despite significant therapeutic advancements, resistance to systemic antineoplastic agents remains an important obstacle, highlighting the need for innovative screening tools to tailor patient-specific treatment. This review explores the application of patient-derived tumor organoids (PDTOs), three-dimensional, self-organizing models derived from patient tumor samples, as screening tools for drug resistance in CRC. PDTOs offer unique advantages over traditional models by recapitulating the tumor architecture, cellular heterogeneity, and genomic landscape and are a valuable ex vivo predictive drug screening tool. This review provides an overview of the current literature surrounding the use of PDTOs as an instrument for predicting therapy responses in CRC. We also explore more complex models, such as co-cultures with important stromal cells, such as cancer-associated fibroblasts, and organ-on-a-chip models. Furthermore, we discuss the use of PDTOs for drug repurposing, offering a new approach to identify the existing drugs effective against drug-resistant CRC. Additionally, we explore how PDTOs serve as models to gain insights into drug resistance mechanisms, using newer techniques, such as single-cell RNA sequencing and CRISPR-Cas9 genome editing. Through this review, we aim to highlight the potential of PDTOs in advancing our understanding of predicting therapy responses, drug resistance, and biomarker identification in CRC management. [ABSTRACT FROM AUTHOR]
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- 2024
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18. The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer.
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Awah, Chidiebere U., Mun, Joo Sun, Paragodaarachchi, Aloka, Boylu, Baris, Ochu, Chika, Matsui, Hiroshi, and Ogunwobi, Olorunseun O.
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BREAST cancer prognosis , *THERAPEUTIC use of antineoplastic agents , *RESEARCH funding , *CANCER invasiveness , *BREAST tumors , *TRANSCRIPTION factors , *TREATMENT effectiveness , *IN vivo studies , *METASTASIS , *MESSENGER RNA , *NUCLEOTIDES , *MICE , *ANIMAL experimentation , *DRUG development , *SURVIVAL analysis (Biometry) , *DRUG tolerance , *SEQUENCE analysis , *DISEASE progression - Abstract
Simple Summary: The overexpression of c-MYC is implicated in many cancers, and it drives the tumors' aggressiveness and metastatic progression, but there is no clinically approved drug that targets MYC. We discovered that the MYC mRNA is stabilized by the poly U sequences on its 3′UTR. We engineered these stable elements into unstable forms in a way such that they degraded the target MYC mRNA through a process called nonsense-mediated decay. We developed the drug 3′UTRMYC1-18 and evaluated its therapeutic efficacy in a metastatic model of c-MYC-driven TNBC in vivo by delivering it with iron oxide nanocages. The constructs inhibited primary and metastatic lung and liver cancers by degrading the c-MYC-STAT5A/5B-PD-L1 complex and achieved significant survival outcomes. The in vivo data strongly suggests that this new drug is therapeutically effective in inhibiting c-MYC-driven triple-negative breast cancer and metastatic tumors. The drug was well tolerated and represents a new arsenal to target the deadly TNBC and will offer hope to patients who need it. c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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19. Radiosynthesis and Preclinical Evaluation of 18 F-Labeled Estradiol Derivatives with Different Lipophilicity for PET Imaging of Breast Cancer.
- Author
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Friedel, Anna, Prante, Olaf, and Maschauer, Simone
- Subjects
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BREAST tumor diagnosis , *CLINICAL drug trials , *BIOLOGICAL models , *IN vitro studies , *RADIOPHARMACEUTICALS , *RESEARCH funding , *BREAST tumors , *ANTINEOPLASTIC agents , *POSITRON emission tomography , *TREATMENT effectiveness , *IN vivo studies , *CANCER cell culture , *RADIOISOTOPES , *DESCRIPTIVE statistics , *ESTRADIOL , *MICE , *CELL lines , *ANIMAL experimentation , *MOLECULAR structure , *FLUORINE isotopes , *DRUG development , *COMPARATIVE studies , *PHARMACODYNAMICS - Abstract
Simple Summary: Breast cancer is one of the most prevalent forms of cancer diagnosed in women worldwide. Since the estradiol receptor (ER) is overexpressed in 75% of breast tumors, it is a reasonable target for tumor diagnosis and therapy. This study focuses on the development and preclinical evaluation of readily synthesized 18F-labeled estradiol derivatives with different lipophilicity. The least hydrophilic derivative, 18F-TA-Glyco-EE, showed the highest cellular uptake in ER-positive breast cancer cells. The in vivo PET imaging of breast tumor-bearing mice demonstrated the desired rapid clearance of the tracer from the excretory organ through the liver. The in vitro autoradiography of ER-positive tumor sections confirmed the high specific binding of 18F-TA-Glyco-EE. In conclusion, 18F-TA-Glyco-EE may be a promising candidate for imaging of ER-positive breast cancer. About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER− MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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20. Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson's Disease.
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Khaspekov, Leonid G. and Illarioshkin, Sergey N.
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PARKINSON'S disease , *CANNABINOID receptors , *DRUG development , *CENTRAL nervous system , *DRUG design - Abstract
The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson's disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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21. Influence of Solvent Polarity on the Conformer Ratio of Bicalutamide in Saturated Solutions: Insights from NOESY NMR Analysis and Quantum-Chemical Calculations.
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Sobornova, Valentina V., Belov, Konstantin V., Krestyaninov, Michael A., and Khodov, Ilya A.
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POLAR solvents , *DIHEDRAL angles , *HYDROGEN bonding , *DRUG development , *SOLVENTS , *CONFORMATIONAL analysis - Abstract
The study presents a thorough and detailed analysis of bicalutamide's structural and conformational properties. Quantum chemical calculations were employed to explore the conformational properties of the molecule, identifying significant energy differences between conformers. Analysis revealed that hydrogen bonds stabilise the conformers, with notable variations in torsion angles. Conformers were classified into 'closed' and 'open' types based on the relative orientation of the cyclic fragments. NOE spectroscopy in different solvents (CDCl3 and DMSO-d6) was used to study the conformational preferences of the molecule. NOESY experiments provided the predominance of 'closed' conformers in non-polar solvents and a significant presence of 'open' conformers in polar solvents. The proportions of open conformers were 22.7 ± 3.7% in CDCl3 and 59.8 ± 6.2% in DMSO-d6, while closed conformers accounted for 77.3 ± 3.7% and 40.2 ± 6.2%, respectively. This comprehensive study underscores the solvent environment's impact on its structural behaviour. The findings significantly contribute to a deeper understanding of conformational dynamics, stimulating further exploration in drug development. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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22. New Target(s) for RNF43 Regulation: Implications for Therapeutic Strategies.
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Nag, Jeetendra Kumar, Appasamy, Priyanga, Malka, Hodaya, Sedley, Shoshana, and Bar-Shavit, Rachel
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- *
GASTROINTESTINAL tumors , *PROTEASE-activated receptors , *BIOTHERAPY , *COLON cancer , *DRUG development , *UBIQUITIN ligases , *G protein coupled receptors - Abstract
Cancer cells depend on specific oncogenic pathways or present a genetic alteration that leads to a particular disturbance. Still, personalized and targeted biological therapy remains challenging, with current efforts generally yielding disappointing results. Carefully assessing onco-target molecular pathways can, however, potently assist with such efforts for the selection of patient populations that would best respond to a given drug treatment. RNF43, an E3 ubiquitin ligase that negatively regulates Wnt/frizzled (FZD) receptors by their ubiquitination, internalization, and degradation, controls a key pathway in cancer. Recently, additional target proteins of RNF43 were described, including p85 of the PI3K/AKT/mTOR signaling pathway and protease-activated receptor 2 (PAR2), a G-protein-coupled receptor that potently induces β-catenin stabilization, independent of Wnts. RNF43 mutations with impaired E3 ligase activity were found in several types of cancers (e.g., gastrointestinal system tumors and endometrial and ovarian cancer), pointing to a high dependency on FZD receptors and possibly PAR2 and the PI3K/AKT/mTOR signaling pathway. The development of drugs toward these targets is essential for improved treatment of cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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23. Synthetic mRNAs Containing Minimalistic Untranslated Regions Are Highly Functional In Vitro and In Vivo.
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Mamaghani, Shahab, Penna, Rocco Roberto, Frei, Julia, Wyss, Conrad, Mellett, Mark, Look, Thomas, Weiss, Tobias, Guenova, Emmanuella, Kündig, Thomas M., Lauchli, Severin, and Pascolo, Steve
- Subjects
- *
GLOBIN genes , *VACCINE approval , *GENETIC transcription , *DRUG development , *GENETIC translation - Abstract
Synthetic mRNA produced by in vitro transcription (ivt mRNA) is the active pharmaceutical ingredient of approved anti-COVID-19 vaccines and of many drugs under development. Such synthetic mRNA typically contains several hundred bases of non-coding "untranslated" regions (UTRs) that are involved in the stabilization and translation of the mRNA. However, UTRs are often complex structures, which may complicate the entire production process. To eliminate this obstacle, we managed to reduce the total amount of nucleotides in the UTRs to only four bases. In this way, we generate minimal ivt mRNA ("minRNA"), which is less complex than the usual optimized ivt mRNAs that are contained, for example, in approved vaccines. We have compared the efficacy of minRNA to common augmented mRNAs (with UTRs of globin genes or those included in licensed vaccines) in vivo and in vitro and could demonstrate equivalent functionalities. Our minimal mRNA design will facilitate the further development and implementation of ivt mRNA-based vaccines and therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
24. Identification and Dynamics Understanding of Novel Inhibitors of Peptidase Domain of Collagenase G from Clostridium histolyticum.
- Author
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Anjum, Farah, Hazazi, Ali, Alsaeedi, Fouzeyyah Ali, Bakhuraysah, Maha, Shafie, Alaa, Alshehri, Norah Ali, Hawsawi, Nahed, Ashour, Amal Adnan, Banjer, Hamsa Jameel, Alharthi, Afaf, and Niaz, Maryam Ishrat
- Subjects
COMPUTER-assisted drug design ,MOLECULAR structure ,DRUG discovery ,PRINCIPAL components analysis ,DRUG development ,PEPTIDASE - Abstract
Clostridium histolyticum is a Gram-positive anaerobic bacterium belonging to the Clostridium genus. It produces collagenase, an enzyme involved in breaking down collagen which is a key component of connective tissues. However, antimicrobial resistance (AMR) poses a great challenge in combating infections caused by this bacteria. The lengthy nature of traditional drug development techniques has resulted in a shift to computer-aided drug design and other modern drug discovery approaches. The above method offers a cost-effective means for gathering comprehensive information about how ligands interact with their target proteins. The objective of this study is to create novel, explicit drugs that specifically inhibit the C. histolyticum collagenase enzyme. Through structure-based virtual screening, a library containing 1830 compounds was screened to identify potential drug candidates against collagenase enzymes. Following that, molecular dynamic (MD) simulation was performed in an aqueous solution to evaluate the behavior of protein and ligand in a dynamic environment while density functional theory (DFT) analysis was executed to predict the molecular properties and structure of lead compounds, and the WaterSwap technique was utilized to obtain insights into the drug–protein interaction with water molecules. Furthermore, principal component analysis (PCA) was performed to reveal conformational changes, salt bridges to express electrostatic interaction and protein stability, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) to assess the pharmacokinetics profile of top compounds and control molecules. Three potent drug candidates were identified MSID000001, MSID000002, MSID000003, and the control with a binding score of −10.7 kcal/mol, −9.8 kcal/mol, −9.5 kcal/mol, and −8 kcal/mol, respectively. Furthermore, Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) analysis of the simulation trajectories revealed energy scores of −79.54 kcal/mol, −73.99 kcal/mol, −62.26 kcal/mol, and −70.66 kcal/mol, correspondingly. The pharmacokinetics properties exhibited were under the acceptable range. The compounds hold the potential to be novel drugs; therefore, further investigation needs to be conducted to find out their anti-collagenase action against C. histolyticum infections and antibiotic resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
25. Sodium Selenite Induces Autophagy and Apoptosis in Cervical Cancer Cells via Mitochondrial ROS-Activated AMPK/mTOR/FOXO3a Pathway.
- Author
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Lv, Cunqi, Zeng, Qingyu, Qi, Lei, Wang, Yuanyuan, Li, Jiacheng, Sun, Huixin, Du, Linlin, Hao, Shuxiu, Li, Guijin, Feng, Chen, Zhang, Yu, Wang, Cheng, Wang, Xinshu, Ma, Rong, Wang, Tong, and Li, Qi
- Subjects
APOPTOSIS inhibition ,DRUG development ,HELA cells ,AMP-activated protein kinases ,SELENIUM compounds ,FORKHEAD transcription factors - Abstract
Selenium (Se) is an essential trace element known for its significant role in maintaining human health and mitigating disease progression. Selenium and its compounds exhibit high selective cytotoxicity against tumor cells. However, their anti-cervical cancer (CC) effects and underlying mechanisms have not been fully explored. This study found that sodium selenite (SS) inhibits the viability of HeLa and SiHa cells in a dose- and time-dependent manner. Intraperitoneal injection of 3 and 6 mg/kg SS for 14 days in female nude mice significantly inhibited the growth of HeLa cell xenografts without evident hepatotoxicity or nephrotoxicity. RNA sequencing results indicated that the AMP-activated protein kinase (AMPK), Forkhead box protein O (FOXO), and apoptosis signaling pathways are key regulatory pathways in SS's anti-CC effects, and SS's inhibition of HeLa cell proliferation may be related to autophagy and ROS-induced apoptosis. Further research has revealed that SS induces cell autophagy and apoptosis through the AMPK/mTOR/FOXO3a pathway, characterized by the upregulation of p-AMPK/AMPK, FOXO3a, LC3-II, cleaved-caspase3, and cleaved-PARP and the downregulation of p-mTOR/mTOR and p62. Additionally, SS impaired mitochondrial function, including decreased mitochondrial membrane potential, mitochondrial Ca
2+ overload, and accumulation of mitochondrial reactive oxygen species (mtROS). Pretreatment with Mitoquinone mesylate (Mito Q) and compound C partially reversed SS-induced apoptosis, autophagy, and proliferation inhibition. Pretreatment with 3-methyladenine (3-MA) enhances SS-induced apoptosis and proliferation inhibition in HeLa cells but reverses these effects in SiHa cells. In summary, SS induces apoptosis, autophagy, and proliferation inhibition in HeLa and SiHa cells through the activation of the AMPK/mTOR/FOXO3a signaling pathway via mtROS. Autophagy activation may be a major risk factor for SS-induced apoptosis in SiHa cells but can protect HeLa cells from SS-induced apoptosis. These findings provide new evidence for understanding the molecular mechanisms underlying SS in potential new drug development for CC. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
26. Phytochemical Composition and Toxicological Screening of Anise Myrtle and Lemon Myrtle Using Zebrafish Larvae.
- Author
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Cáceres-Vélez, Paolin Rocio, Ali, Akhtar, Fournier-Level, Alexandre, Dunshea, Frank R., and Jusuf, Patricia Regina
- Subjects
OXIDANT status ,CELL death ,DEGENERATION (Pathology) ,DRUG development ,NATIVE plants ,BRACHYDANIO - Abstract
Plants are an immense source of drugs, and 50% of modern pharmacopeia has a plant origin. With increasing life expectancy in humans, many age-related degenerative diseases converge on oxidative cellular stress pathways. This provides an opportunity to develop broad treatments by targeting the cause of common pathologic cell degeneration. Toxicological effects can be readily assessed in a live animal model system to establish potential fauna for clinical use. Here, we characterized and evaluated the antioxidant potential and toxicological effects of anise myrtle (Syzygium anisatum) and lemon myrtle (Backhousia citriodora) leaves. Using zebrafish larvae, a model for high-throughput pre-clinical in vivo toxicology screening, we identified safe levels of extract exposures for development of future therapeutics. The antioxidant capacity and toxicity were very similar in these two myrtles. The LC
50 -96h for anise myrtle was 284 mg/L, and for lemon myrtle, it was 270 mg/L. These measurements are comparable to ongoing studies we are performing using the same criteria in zebrafish, which allow for robust testing and prioritization of natural fauna for drug development. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
27. Upholding or Breaking the Law of Superposition in Pharmacokinetics.
- Author
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Yousef, Malaz, Yáñez, Jaime A., Löbenberg, Raimar, and Davies, Neal M.
- Subjects
ORAL drug administration ,POISONS ,SUPERPOSITION principle (Physics) ,INTRAVENOUS therapy ,DRUG development - Abstract
The law of superposition underpins first-order linear pharmacokinetic relationships. Most drugs, therefore, after a single dose can be described by first-order or linear processes, which can be superposed to understand multiple-dose regimen behavior. However, there are a number of situations where drugs could display behaviors after multiple dosing that leads to capacity-limited or saturation non-linear kinetics and the law of superposition is overruled. This review presents a practical guide to understand the equations and calculations for single and multiple-dosing regimens after intravenous and oral administration. It also provides the pharmaceutical basis for saturation in ADME processes and the consequent changes in the area under the concentration–time curve, which represents drug exposure that can lead to the modulation of efficacy and/or toxic effects. The pharmacokineticist must implicitly understand the principles of superposition, which are a central tenet of drug behavior and disposition during drug development. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
28. Automated Uniform Spheroid Generation Platform for High Throughput Drug Screening Process.
- Author
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Pong, Kelvin C. C., Lai, Yuen Sze, Wong, Roy Chi Hang, Lee, Alan Chun Kit, Chow, Sam C. T., Lam, Jonathan C. W., Ho, Ho Pui, and Wong, Clarence T. T.
- Subjects
HIGH throughput screening (Drug development) ,BIOLOGICAL systems ,DRUG development ,CELL survival ,CANCER research ,CELL culture - Abstract
Three-dimensional (3D) spheroid models are crucial for cancer research, offering more accurate insights into tumour biology and drug responses than traditional 2D cell cultures. However, inconsistent and low-throughput spheroid production has hindered their application in drug screening. Here, we present an automated high-throughput platform for a spheroid selection, fabrication, and sorting system (SFSS) to produce uniform gelatine-encapsulated spheroids (GESs) with high efficiency. SFSS integrates advanced imaging, analysis, photo-triggered fabrication, and microfluidic sorting to precisely control spheroid size, shape, and viability. Our data demonstrate that our SFSS can produce over 50 GESs with consistent size and circularity in 30 min with over 97% sorting accuracy while maintaining cell viability and structural integrity. We demonstrated that the GESs can be used for drug screening and potentially for various assays. Thus, the SFSS could significantly enhance the efficiency of generating uniform spheroids, facilitating their application in drug development to investigate complex biological systems and drug responses in a more physiologically relevant context. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
29. Electrochemical Probing of Human Liver Subcellular S9 Fractions for Drug Metabolite Synthesis.
- Author
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Medina, Daphne, Omanakuttan, Bhavana, Nguyen, Ricky, Alwarsh, Eman, and Walgama, Charuksha
- Subjects
LIVER microsomes ,STANDARD hydrogen electrode ,DRUG development ,DRUG synthesis ,SULFOTRANSFERASES - Abstract
Human liver subcellular fractions, including liver microsomes (HLM), liver cytosol fractions, and S9 fractions, are extensively utilized in in vitro assays to predict liver metabolism. The S9 fractions are supernatants of human liver homogenates that contain both microsomes and cytosol, which include most cytochrome P450 (CYP) enzymes and soluble phase II enzymes such as glucuronosyltransferases and sulfotransferases. This study reports on the direct electrochemistry and biocatalytic features of redox-active enzymes in S9 fractions for the first time. We investigated the electrochemical properties of S9 films by immobilizing them onto a high-purity graphite (HPG) electrode and performing cyclic voltammetry under anaerobic (Ar-saturated) and aerobic (O
2 -saturated) conditions. The heterogeneous electron transfer rate between the S9 film and the HPG electrode was found to be 14 ± 3 s−1 , with a formal potential of −0.451 V vs. Ag/AgCl reference electrode, which confirmed the electrochemical activation of the FAD/FMN cofactor containing CYP450-reductase (CPR) as the electron receiver from the electrode. The S9 films have also demonstrated catalytic oxygen reduction under aerobic conditions, identical to HLM films attached to similar electrodes. Additionally, we investigated CYP activity in the S9 biofilm for phase I metabolism using diclofenac hydroxylation as a probe reaction and identified metabolic products using liquid chromatography–mass spectrometry (LC-MS). Investigating the feasibility of utilizing liver S9 fractions in such electrochemical assays offers significant advantages for pharmacological and toxicological evaluations of new drugs in development while providing valuable insights for the development of efficient biosensor and bioreactor platforms. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
30. A Comprehensive Review of Biologics in Phase III and IV Clinical Trials for Atopic Dermatitis.
- Author
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Waligóra-Dziwak, Katarzyna, Dańczak-Pazdrowska, Aleksandra, and Jenerowicz, Dorota
- Subjects
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BIOTHERAPY , *ATOPIC dermatitis , *DRUG development , *CLINICAL trials , *DRUG therapy - Abstract
Atopic dermatitis (AD) is a skin condition characterized by significant challenges and a substantial deterioration in the life quality for affected patients. The therapeutic landscape for AD has witnessed a transformative shift with the emergence of biologic therapies. Our focus centers on biologics currently undergoing phase III and IV clinical trials, deeming them to hold the highest potential for significant clinical relevance. To identify biologic drugs under development in phase III and IV clinical trials, we searched ClinicalTrials.gov. Additional relevant trials were identified through JapicCTI/ Japan Registry of Clinical Trials (jRCT) with a citation search. A search in MEDLINE and EMBASE was performed. There have been 76 clinical trials identified concerning biologic drugs: dupilumab (34 trials), lebrikizumab (14 trials), tralokinumab (10 trials), rocatinlimab (7 trials), amlitelimab (2 trials), nemolizumab (6 trials), MG-K10 (1 trial), CM310 (1 trial), 611 (1 trial). A search in MEDLINE revealed 132 articles concerning phase III and IV clinical trials for AD treatment. A total of 39 articles concerned biologic drugs covering 23 clinical trials. A search in EMBASE revealed 268 relevant articles, allowing us to identify results of an additional six clinical trials. The safety and efficacy of these biologics are comprehensively addressed in this review. This comprehensive review aims to explore the current landscape of biologic therapies for AD, delving into the latest research findings, clinical trial outcomes, and the diverse mechanisms of action employed by these novel interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
31. The Antiviral Potential of Perilla frutescens : Advances and Perspectives.
- Author
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Chen, Jing, Zhao, Yi, Cheng, Jie, Wang, Haoran, Pan, Shu, and Liu, Yuwei
- Subjects
- *
PERILLA frutescens , *DRUG bioavailability , *DRUG development , *VIRUS-induced enzymes , *EDIBLE plants , *ANTIVIRAL agents - Abstract
Viruses pose a significant threat to human health, causing widespread diseases and impacting the global economy. Perilla frutescens, a traditional medicine and food homologous plant, is well known for its antiviral properties. This systematic review examines the antiviral potential of Perilla frutescens, including its antiviral activity, chemical structure and pharmacological parameters. Utilizing bioinformatics analysis, we revealed the correlation between Perilla frutescens and antiviral activity, identified overlaps between Perilla frutescens target genes and virus-related genes, and explored related signaling pathways. Moreover, a classified summary of the active components of Perilla frutescens, focusing on compounds associated with antiviral activity, provides important clues for optimizing the antiviral drug development of Perilla frutescens. Our findings indicate that Perilla frutescens showed a strong antiviral effect, and its active ingredients can effectively inhibit the replication and spread of a variety of viruses in this review. The antiviral mechanisms of Perilla frutescens may involve several pathways, including enhanced immune function, modulation of inflammatory responses, and inhibition of key enzyme activities such as viral replicase. These results underscore the potential antiviral application of Perilla frutescens as a natural plant and provide important implications for the development of new antiviral drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
32. Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development.
- Author
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Thein, Kyaw Z., Myat, Yin M., Park, Byung S., Panigrahi, Kalpana, and Kummar, Shivaani
- Subjects
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THERAPEUTIC use of antineoplastic agents , *MITOGEN-activated protein kinases , *GENOMICS , *ANTINEOPLASTIC agents , *PROGRAMMED death-ligand 1 , *PROTEIN-tyrosine kinase inhibitors , *TUMOR markers , *DRUG approval , *IMMUNE checkpoint inhibitors , *ONCOGENES , *TUMORS , *DRUG development , *GENETIC mutation , *INDIVIDUALIZED medicine - Abstract
Simple Summary: Precision oncology is at the forefront of personalized cancer care, utilizing tumor-agnostic therapies that target specific biomarkers, such as tumor mutational burden, microsatellite instability, mutations, or fusions, regardless of cancer type. This review aims to provide a comprehensive summary of the immune checkpoint inhibitors and the targeted therapies approved by the US Food and Drug Administration (FDA) for tumor-agnostic use. We thoroughly reviewed pembrolizumab, dostarlimab, larotrectinib, entrectinib, selpercatinib, dabrafenib plus trametinib, and trastuzumab deruxtecan across eight indications, detailing their efficacy, toxicity, and regulatory history. Additionally, we highlight the critical role of biostatistics in designing the clinical trials necessary for evaluating these treatments. These insights advance our understanding of biomarker-driven approaches, guide future research directions, and support the development of more effective, personalized cancer treatments across diverse histology. The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
33. Optimizing Ex Vivo CAR-T Cell-Mediated Cytotoxicity Assay through Multimodality Imaging.
- Author
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Foulke, John G., Chen, Luping, Chang, Hyeyoun, McManus, Catherine E., Tian, Fang, and Gu, Zhizhan
- Subjects
- *
HIGH throughput screening (Drug development) , *T cells , *DIAGNOSTIC imaging , *IMMUNODIAGNOSIS , *IN vivo studies , *CELL lines , *RNA , *DRUG development , *CELL surface antigens , *DRUG discovery , *SEQUENCE analysis - Abstract
Simple Summary: CAR-T cell therapies are highly effective for treating cancers, particularly liquid tumors, and are now being tested in clinical trials for solid tumors. The FDA's initiative for new drug discovery methods highlights the need for precise ex vivo assays for CAR-T development. Current assays have drawbacks, such as using radioactive materials and lacking real-time measurement and automation. To improve these assays, we used multimodality imaging (bioluminescence, impedance, phase contrast, and fluorescence) to monitor CAR-T cells with cancer cells in real-time. We also adjusted cell ratios for optimal results. Our optimized assay showed that CAR-T cells effectively attacked cancer cells, providing precise, reliable, and high-throughput measurements. CAR-T cell-based therapies have demonstrated remarkable efficacy in treating malignant cancers, especially liquid tumors, and are increasingly being evaluated in clinical trials for solid tumors. With the FDA's initiative to advance alternative methods for drug discovery and development, full human ex vivo assays are increasingly essential for precision CAR-T development. However, prevailing ex vivo CAR-T cell-mediated cytotoxicity assays are limited by their use of radioactive materials, lack of real-time measurement, low throughput, and inability to automate, among others. To address these limitations, we optimized the assay using multimodality imaging methods, including bioluminescence, impedance tracking, phase contrast, and fluorescence, to track CAR-T cells co-cultured with CD19, CD20, and HER2 luciferase reporter cancer cells in real-time. Additionally, we varied the ratio of CAR-T cells to cancer cells to determine optimal cytotoxicity readouts. Our findings demonstrated that the CAR-T cell group effectively attacked cancer cells, and the optimized assay provided superior temporal and spatial precision measurements of ex vivo CAR-T killing of cancer cells, confirming the reliability, consistency, and high throughput of the optimized assay. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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34. Functional Characterization of Six Eukaryotic Translation Initiation Factors of Toxoplasma gondii Using the CRISPR-Cas9 System.
- Author
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Kou, Yong-Jie, Gao, Jin, Li, Rui, Ma, Zhi-Ya, Elsheikha, Hany M., Wu, Xiao-Jing, Zheng, Xiao-Nan, Wang, Meng, and Zhu, Xing-Quan
- Subjects
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INITIATION factors (Biochemistry) , *TOXOPLASMA gondii , *APICOMPLEXA , *CRISPRS , *GENETIC translation , *VACCINE development , *DRUG development - Abstract
Eukaryotic translation initiation factors (eIFs) are crucial for initiating protein translation and ensuring the correct assembly of mRNA-ribosomal subunit complexes. In this study, we investigated the effects of deleting six eIFs in the apicomplexan parasite Toxoplasma gondii using the CRISPR-Cas9 system. We determined the subcellular localization of these eIFs using C-terminal endogenous tagging and immunofluorescence analysis. Four eIFs (RH::315150-6HA, RH::286090-6HA, RH::249370-6HA, and RH::211410-6HA) were localized in the cytoplasm, while RH::224235-6HA was localized in the apicoplast. Additionally, RH::272640-6HA was found in both the basal complex and the cytoplasm of T. gondii. Functional characterization of the six RHΔeIFs strains was conducted using plaque assay, cell invasion assay, intracellular growth assay and egress assay in vitro, and virulence assay in mice. Disruption of five eIF genes (RHΔ315150, RHΔ272640, RHΔ249370, RHΔ211410, and RHΔ224235) did not affect the ability of the T. gondii RH strain to invade, replicate, form plaques and egress in vitro, or virulence in Kunming mice (p > 0.05). However, the RHΔ286090 strain showed slightly reduced invasion efficiency and virulence (p < 0.01) compared to the other five RHΔeIFs strains and the wild-type strain. The disruption of the TGGT1_286090 gene significantly impaired the ability of tachyzoites to differentiate into bradyzoites in both type I RH and type II Pru strains. These findings reveal that the eukaryotic translation initiation factor TGGT1_286090 is crucial for T. gondii bradyzoite differentiation and may serve as a potential target for drug development and an attenuated vaccine against T. gondii. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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35. MRAP2a Binds and Modulates Activity and Localisation of Prokineticin Receptor 1 in Zebrafish.
- Author
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Fullone, Maria Rosaria, Maftei, Daniela, Vincenzi, Martina, Lattanzi, Roberta, and Miele, Rossella
- Subjects
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MELANOCORTIN receptors , *BRACHYDANIO , *MEMBRANE proteins , *DRUG development , *STAT proteins - Abstract
The prokineticin system plays a role in hypothalamic neurons in the control of energy homeostasis. Prokineticin receptors (PKR1 and PKR2), like other G-protein-coupled receptors (GPCRs) are involved in the regulation of energy intake and expenditure and are modulated by the accessory membrane protein 2 of the melanocortin receptor (MRAP2). The aim of this work is to characterise the interaction and regulation of the non-melanocortin receptor PKR1 by MRAP2a in zebrafish (zMRAP2a) in order to use zebrafish as a model for the development of drugs targeting accessory proteins that can alter the localisation and activity of GPCRs. To this end, we first showed that zebrafish PKR1 (zPKR1) is able to interact with both zMRAP2a and human MRAP2 (hMRAP2). This interaction occurs between the N-terminal region of zPKR1 and the C-terminal domain of zMRAP2a, which shows high sequence identity with hMRAP2 and a similar propensity for dimer formation. Moreover, we demonstrated that in Chinese hamster ovary (CHO) cells, zMRAP2a or hMRAP2 are able to modulate zPKR1 activation induced by zebrafish PK2 (zPK2) resulting in an impaired ERK and STAT3 activation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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36. Research on Artificial-Intelligence-Assisted Medicine: A Survey on Medical Artificial Intelligence.
- Author
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Gou, Fangfang, Liu, Jun, Xiao, Chunwen, and Wu, Jia
- Subjects
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STANDARD of living , *ARTIFICIAL intelligence , *MEDICAL personnel , *QUALITY of service , *COMPUTER-assisted image analysis (Medicine) - Abstract
With the improvement of economic conditions and the increase in living standards, people's attention in regard to health is also continuously increasing. They are beginning to place their hopes on machines, expecting artificial intelligence (AI) to provide a more humanized medical environment and personalized services, thus greatly expanding the supply and bridging the gap between resource supply and demand. With the development of IoT technology, the arrival of the 5G and 6G communication era, and the enhancement of computing capabilities in particular, the development and application of AI-assisted healthcare have been further promoted. Currently, research on and the application of artificial intelligence in the field of medical assistance are continuously deepening and expanding. AI holds immense economic value and has many potential applications in regard to medical institutions, patients, and healthcare professionals. It has the ability to enhance medical efficiency, reduce healthcare costs, improve the quality of healthcare services, and provide a more intelligent and humanized service experience for healthcare professionals and patients. This study elaborates on AI development history and development timelines in the medical field, types of AI technologies in healthcare informatics, the application of AI in the medical field, and opportunities and challenges of AI in the field of medicine. The combination of healthcare and artificial intelligence has a profound impact on human life, improving human health levels and quality of life and changing human lifestyles. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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37. Readers of RNA Modification in Cancer and Their Anticancer Inhibitors.
- Author
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Li, Fengli and Li, Wenjin
- Subjects
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RNA modification & restriction , *NON-coding RNA , *SMALL molecules , *DRUG development , *EPIGENETICS - Abstract
Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have turned their attention toward epigenetics, offering a novel perspective in this realm. The investigation of epigenetics has brought RNA readers to the forefront, as they play pivotal roles in recognizing and regulating RNA functions. Recently, the development of inhibitors targeting these RNA readers has emerged as a focal point in research and holds promise for further strides in targeted therapy. In this review, we comprehensively summarize various types of inhibitors targeting RNA readers, including non-coding RNA (ncRNA) inhibitors, small-molecule inhibitors, and other potential inhibitors. We systematically elucidate their mechanisms in suppressing cancer progression by inhibiting readers, aiming to present inhibitors of readers at the current stage and provide more insights into the development of anticancer drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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38. mRCat: A Novel CatBoost Predictor for the Binary Classification of mRNA Subcellular Localization by Fusing Large Language Model Representation and Sequence Features.
- Author
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Wang, Xiao, Yang, Lixiang, and Wang, Rong
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LANGUAGE models , *GENETIC regulation , *MESSENGER RNA , *PROTEIN synthesis , *DRUG development , *BOOSTING algorithms - Abstract
The subcellular localization of messenger RNAs (mRNAs) is a pivotal aspect of biomolecules, tightly linked to gene regulation and protein synthesis, and offers innovative insights into disease diagnosis and drug development in the field of biomedicine. Several computational methods have been proposed to predict the subcellular localization of mRNAs within cells. However, there remains a deficiency in the accuracy of these predictions. In this study, we propose an mRCat predictor based on the gradient boosting tree algorithm specifically to predict whether mRNAs are localized in the nucleus or in the cytoplasm. This predictor firstly uses large language models to thoroughly explore hidden information within sequences and then integrates traditional sequence features to collectively characterize mRNA gene sequences. Finally, it employs CatBoost as the base classifier for predicting the subcellular localization of mRNAs. The experimental validation on an independent test set demonstrates that mRCat obtained accuracy of 0.761, F1 score of 0.710, MCC of 0.511, and AUROC of 0.751. The results indicate that our method has higher accuracy and robustness compared to other state-of-the-art methods. It is anticipated to offer deep insights for biomolecular research. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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39. Advanced Kidney Models In Vitro Using the Established Cell Line Renal Proximal Tubular Epithelial/Telomerase Reverse Transcriptase1 for Nephrotoxicity Assays.
- Author
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Lacueva-Aparicio, Alodia, Martínez-Gimeno, Laura, Torcal, Pilar, Ochoa, Ignacio, and Giménez, Ignacio
- Subjects
- *
PROXIMAL kidney tubules , *DRUG development , *CLINICAL drug trials , *SHEARING force , *CELL physiology - Abstract
Nephrotoxicity stands as one of the most limiting effects in the development and validation of new drugs. The kidney, among the organs evaluated in toxicity assessments, has a higher susceptibility, with nephrotoxic potential frequently evading detection until late in clinical trials. Traditional cell culture, which has been widely used for decades, does not recapitulate the structure and complexity of the native tissue, which can affect cell function, and the response to cytotoxins does not resemble what occurs in the kidney. In the current study, we aimed to address these challenges by creating in vitro kidney models that faithfully biomimic the dynamics of the renal proximal tubule, using the well-established RPTEC/TERT1 cell line. For doing so, two models were developed, one recreating tubule-like structures (2.5D model) and the other using microfluidic technology (kidney-on-a-chip). The 2.5D model allowed tubular structures to be generated in the absence of hydrogels, and the kidney-on-a-chip model allowed shear stress to be applied to the cell culture, which is a physiological stimulus in the renal tissue. After characterization of both models, different nephrotoxic compounds such as cisplatin, tacrolimus, and daunorubicin were used to study cell responses after treatment. The developed models in our study could be a valuable tool for pre-clinical nephrotoxic testing of drugs and new compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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40. The United States Food and Drug Administration's Platform Technology Designation to Expedite the Development of Drugs.
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Niazi, Sarfaraz K.
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DRUG approval , *DRUG development , *GENE therapy , *DRUG prices , *REGULATORY approval - Abstract
Drug development costs can be significantly reduced if proven "platform" technologies are allowed to be used without having to validate their use. The most recent US Food and Drug Administration (FDA) guideline brings more clarity, as well as a greater focus on the most complex technologies that can now be used for faster drug development. The FDA has highlights the use of lipid nanoparticles (LNPs) to package and deliver mRNA vaccines, gene therapy, and short (2–20 length) synthetic nucleotides (siRNA). Additionally, monoclonal antibody cell development is targeted. The FDA provides a systematic process of requesting platform status to benefit from its advantages. It brings advanced science and rationality into regulatory steps for the FDA's approval of drugs and biologicals. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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41. Conquering the beyond Rule of Five Space with an Optimized High-Throughput Caco-2 Assay to Close Gaps in Absorption Prediction.
- Author
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Muschong, Patricia, Awwad, Khader, Price, Edward, Mezler, Mario, and Weinheimer, Manuel
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DRUG development , *PERMEABILITY , *ABSORPTION , *PROTEOLYSIS , *BIOAVAILABILITY - Abstract
Current drug development tends towards complex chemical molecules, referred to as "beyond rule of five" (bRo5) compounds, which often exhibit challenging physicochemical properties. Measuring Caco-2 permeability of those compounds is difficult due to technical limitations, including poor recovery and detection sensitivity. We implemented a novel assay, with optimized incubation and analytics, to measure permeability close to equilibrium. In this setup an appropriate characterization of permeability for bRo5 compounds is achievable. This equilibrated Caco-2 assay was verified with respect to data validity, compound recovery, and in vitro to in vivo correlation for human absorption. Compared to a standard assay, it demonstrated comparable performance in predicting the human fraction absorbed (fa) for reference compounds. The equilibrated assay also successfully characterized the permeability of more than 90% of the compounds analyzed, the majority of which were bRo5 (68%). These compounds could not be measured using the standard assay. Permeability and efflux ratio (ER) were highly predictive for in vivo absorption for a large set of internal bRo5 compounds. Reference cut-offs enabled the correct classification of high, moderate, and low absorption. This optimized equilibrated Caco-2 assay closes the gap for a high-throughput cellular permeability method in the bRo5 chemical space. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
42. Expanding Role of Endogenous Biomarkers for Assessment of Transporter Activity in Drug Development: Current Applications and Future Horizon.
- Author
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Arya, Vikram, Ma, Joseph D., and Kvitne, Kine Eide
- Subjects
- *
DRUG development , *BIOMARKERS , *DISEASE progression , *FORECASTING - Abstract
The evaluation of transporter-mediated drug–drug interactions (DDIs) during drug development and post-approval contributes to benefit–risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
43. Pharmacogenomics: A Genetic Approach to Drug Development and Therapy.
- Author
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Qahwaji, Rowaid, Ashankyty, Ibraheem, Sannan, Naif S., Hazzazi, Mohannad S., Basabrain, Ammar A., and Mobashir, Mohammad
- Subjects
- *
DRUG therapy , *DRUG development , *MEDICAL sciences , *PHARMACOKINETICS , *PHARMACODYNAMICS - Abstract
The majority of the well-known pharmacogenomics research used in the medical sciences contributes to our understanding of medication interactions. It has a significant impact on treatment and drug development. The broad use of pharmacogenomics is required for the progress of therapy. The main focus is on how genes and an intricate gene system affect the body's reaction to medications. Novel biomarkers that help identify a patient group that is more or less likely to respond to a certain medication have been discovered as a result of recent developments in the field of clinical therapeutics. It aims to improve customized therapy by giving the appropriate drug at the right dose at the right time and making sure that the right prescriptions are issued. A combination of genetic, environmental, and patient variables that impact the pharmacokinetics and/or pharmacodynamics of medications results in interindividual variance in drug response. Drug development, illness susceptibility, and treatment efficacy are all impacted by pharmacogenomics. The purpose of this work is to give a review that might serve as a foundation for the creation of new pharmacogenomics applications, techniques, or strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. Adenosine Monophosphate as a Metabolic Adjuvant Enhances Antibiotic Efficacy against Drug-Resistant Bacterial Pathogens.
- Author
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Zhang, Wenxuan, Wu, Zhenyi, Maituersong, Zulifukeer, Wang, Ting, and Su, Yubin
- Subjects
- *
ADENOSINE monophosphate , *DRUG resistance in bacteria , *KREBS cycle , *DRUG resistance in microorganisms , *DRUG development - Abstract
Global bacterial infections are on the rise, and drug resistance to bacteria is gradually rendering existing antibiotics ineffective. Therefore, the discovery of new strategies is urgently needed. Cellular metabolism is a key factor in the regulation of bacterial drug resistance, which cannot be separated from the utilization of energetic substances, suggesting that energetic substances may be associated with bacterial drug resistance. In this study, we found that adenosine monophosphate (AMP) can enhance the bactericidal effect of gentamicin against gentamicin-resistant Staphylococcus aureus. This synergistic effect can be generalized for use with different antibiotics and Gram-positive or Gram-negative bacteria. We also validated that the mechanism of AMP reversal of antibiotic resistance involves enhancing the proton motive force via the tricarboxylic acid cycle to increase antibiotic uptake. Simultaneously, AMP increases oxidative stress-induced cell death. This study presents a strategy for adopting low-dose antibiotics to control drug-resistant bacteria, which is important for future drug development and bacterial control. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
45. From Drug Discovery to Drug Approval: A Comprehensive Review of the Pharmacogenomics Status Quo with a Special Focus on Egypt.
- Author
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Elgarhy, Fadya M., Borham, Abdallah, Alziny, Noha, AbdElaal, Khlood R., Shuaib, Mahmoud, Musaibah, Abobaker Salem, Hussein, Mohamed Ali, and Abdelnaser, Anwar
- Subjects
- *
DRUG discovery , *DRUG therapy , *DRUG development , *SINGLE nucleotide polymorphisms , *INDIVIDUALIZED medicine , *PHARMACOGENOMICS - Abstract
Pharmacogenomics (PGx) is the hope for the full optimization of drug therapy while minimizing the accompanying adverse drug events that cost billions of dollars annually. Since years before the century, it has been known that inter-individual variations contribute to differences in specific drug responses. It is the bridge to what is well-known today as "personalized medicine". Addressing the drug's pharmacokinetics and pharmacodynamics is one of the features of this science, owing to patient characteristics that vary on so many occasions. Mainly in the liver parenchymal cells, intricate interactions between the drug molecules and enzymes family of so-called "Cytochrome P450" occur which hugely affects how the body will react to the drug in terms of metabolism, efficacy, and safety. Single nucleotide polymorphisms, once validated for a transparent and credible clinical utility, can be used to guide and ensure the succession of the pharmacotherapy plan. Novel tools of pharmacoeconomics science are utilized extensively to assess cost-effective pharmacogenes preceding the translation to the bedside. Drug development and discovery incorporate a drug-gene perspective and save more resources. Regulations and laws shaping the clinical PGx practice can be misconceived; however, these pre-/post approval processes ensure the product's safety and efficacy. National and international regulatory agencies seek guidance on maintaining conduct in PGx practice. In this patient-centric era, social and legal considerations manifest in a way that makes them unavoidable, involving patients and other stakeholders in a deliberate journey toward utmost patient well-being. In this comprehensive review, we contemporarily addressed the scientific leaps in PGx, along with various challenges that face the proper implementation of personalized medicine in Egypt. These informative insights were drawn to serve what the Egyptian population, in particular, would benefit from in terms of knowledge and know-how while maintaining the latest global trends. Moreover, this review is the first to discuss various modalities and challenges faced in Egypt regarding PGx, which we believe could be used as a pilot piece of literature for future studies locally, regionally, and internationally. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
46. Advancing Virtual Bioequivalence for Orally Administered Drug Products: Methodology, Real-World Applications and Future Outlook.
- Author
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Kollipara, Sivacharan, Martins, Frederico Severino, Jereb, Rebeka, Krajcar, Dejan, and Ahmed, Tausif
- Subjects
- *
DRUG development , *BIOPHARMACEUTICS , *PHARMACOKINETICS , *RISK assessment , *GENERIC drugs , *DECISION making - Abstract
Bioequivalence studies are pivotal in generic drug development wherein therapeutic equivalence is provided with an innovator product. However, bioequivalence studies represent significant complexities due to the interplay of multiple factors related to drug, formulation, physiology, and pharmacokinetics. Approaches such as physiologically based biopharmaceutics modeling (PBBM) can enable virtual bioequivalence (VBE) assessment through appropriately developed and validated models. Such models are now being extensively used for bioequivalence risk assessment, internal decision-making, and the evaluation of drug and formulation factors related to bioequivalence. Depiction of the above-mentioned factors through the incorporation of variability and development of a virtual population for bioequivalence assessment is of paramount importance in utilizing such models. In this manuscript, we have portrayed our current understanding of VBE. A detailed explanation was provided with respect to study designs, in vivo variability, and the impact of physiological, drug, and formulation factors on the development of the population for VBE. Furthermore, strategies are suggested to incorporate variability in GastroPlus with an emphasis on intra-subject and inter-occasion variability. Two industrial case studies pertaining to immediate and modified release formulation were portrayed wherein VBE was utilized for decision-making and regulatory justification. Finally, regulatory understanding in the area of VBE, along with future perspectives, was detailed. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
47. Critical Appraisal and Future Challenges of Artificial Intelligence and Anticancer Drug Development.
- Author
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Chamorey, Emmanuel, Gal, Jocelyn, Mograbi, Baharia, and Milano, Gérard
- Subjects
- *
DRUG approval , *DRUG discovery , *ARTIFICIAL intelligence , *MACHINE learning , *DRUG development - Abstract
The conventional rules for anti-cancer drug development are no longer sufficient given the relatively limited number of patients available for therapeutic trials. It is thus a real challenge to better design trials in the context of new drug approval for anti-cancer treatment. Artificial intelligence (AI)-based in silico trials can incorporate far fewer but more informative patients and could be conducted faster and at a lower cost. AI can be integrated into in silico clinical trials to improve data analysis, modeling and simulation, personalized medicine approaches, trial design optimization, and virtual patient generation. Health authorities are encouraged to thoroughly review the rules for setting up clinical trials, incorporating AI and in silico methodology once they have been appropriately validated. This article also aims to highlight the limits and challenges related to AI and machine learning. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
48. Identification of Novel Isatin Derivative Bearing a Nitrofuran Moiety as Potent Multi-Isoform Aldehyde Dehydrogenase Inhibitor.
- Author
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Gowda, Krishne, Raza, Asif, Vangala, Venugopal, Lone, Nazir Ahmad, Jyh Ming Lin, Singh, Jaikee Kumar, Srivastava, Sandeep Kumar, Schell, Todd D., Robertson, Gavin P., Amin, Shantu, and Sharma, Arun K.
- Abstract
Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
49. Discovering Potential in Non-Cancer Medications: A Promising Breakthrough for Multiple Myeloma Patients.
- Author
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Al-Odat, Omar S., Nelson, Emily, Budak-Alpdogan, Tulin, Jonnalagadda, Subash C., Desai, Dhimant, and Pandey, Manoj K.
- Subjects
- *
THERAPEUTIC use of antineoplastic agents , *MULTIPLE myeloma , *COMPUTER-assisted molecular modeling , *COST effectiveness , *ASPIRIN , *ANTINEOPLASTIC agents , *DRUG repositioning , *STATINS (Cardiovascular agents) , *DRUG discovery - Abstract
Simple Summary: Multiple myeloma (MM) is a type of cancer that affects the blood and bone marrow. Each individual diagnosed with MM will inevitably experience a relapse or develop resistance to the prescribed treatment. The development of new pharmaceuticals is an expensive and time-consuming process, which requires the investigation of more efficient approaches. This review article explores the potential of repurposing current drugs, originally designed for other conditions, for the treatment of MM. This approach is more efficient and economical in comparison to the process of developing new drugs from scratch. For instance, thalidomide, initially used for several medical ailments, has shown effectiveness in treating MM. This study emphasizes the potential of repurposing common drugs, such as aspirin and statins, for the treatment of MM. This approach not only speeds up the availability of new treatments but also offers hope for better outcomes for patients with MM. Future investigations will give priority to determining the most effective dosages and integrating these repurposed drugs with traditional therapy to improve their effectiveness. MM is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse; therefore, advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which are typically a major concern for MM patients. The utilization of pre-existing non-cancer drugs for various myeloma treatments presents a highly efficient and cost-effective strategy, considering their prior preclinical and clinical development. The drugs have shown promising potential in targeting key pathways associated with MM progression and resistance. Thalidomide exemplifies the success that can be achieved through this strategy. This review delves into the current trends, the challenges faced by conventional therapies for MM, and the importance of repurposing drugs for MM. This review highlights a noncomprehensive list of conventional therapies that have potentially significant anti-myeloma properties and anti-neoplastic effects. Additionally, we offer valuable insights into the resources that can help streamline and accelerate drug repurposing efforts in the field of MM. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Computational Approach for the Development of pH-Selective PD-1/PD-L1 Signaling Pathway Inhibition in Fight with Cancer.
- Author
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McDowell, Roderick C., Booth, Jordhan D., McGowan, Allyson, Kolodziejczyk, Wojciech, Hill, Glake A., Banerjee, Santanu, Feng, Manliang, and Kapusta, Karina
- Subjects
- *
COMPUTER-assisted molecular modeling , *RESEARCH funding , *INVESTIGATIONAL drugs , *CELLULAR signal transduction , *IMMUNE checkpoint inhibitors , *CELL lines , *MOLECULAR structure , *DRUG efficacy , *TUMORS , *DRUG development , *ACID-base equilibrium , *CARCINOGENESIS , *PHARMACODYNAMICS - Abstract
Simple Summary: Despite considerable progress in cancer research and treatment, cancer continues to be a major health challenge, often requiring invasive treatments with substantial side effects. Immuno-therapy, which targets the immune system's PD-1/PD-L1 pathway, represents a promising alternative. This critical pathway allows cancer cells to avoid immune destruction by inhibiting T-cells. Our study employs computational techniques to develop inhibitors that block the PD-L1 pathway, specifically in the acidic environment of tumors. By analyzing around 10,000 natural compounds, we identified a potential pH-selective inhibitor that shows greater effectiveness in the acidic conditions typical of cancerous tissues. This research suggests a novel approach for experimental groups to explore, focusing on developing targeted, pH-dependent inhibitors that could mark a significant step in enhancing the precision and effectiveness of immunotherapy treatments, potentially revolutionizing cancer therapy. Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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