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Formulation scale-up remains a major hurdle in drug development in part because preliminary formulation research efforts rarely consider the challenges of scaling up production for commercialization. This Perspective outlines considerations around scalability that can be incorporated into formulation design work in order to increase the chances of successful translation. Both technical (unit operations, excipient selection, scaling principles) and non-technical (funding, publications, and personnel) considerations are discussed, with a focus on lab-scale work by academic researchers. [Display omitted] [ABSTRACT FROM AUTHOR]

In this contribution to the Orations - New Horizons of the Journal of Controlled Release, I discuss the research that we have conducted on gut hormone stimulation as a therapeutic strategy in oral peptide delivery. One of the greatest challenges in oral drug delivery involves the development of new drug delivery systems that enable the absorption of therapeutic peptides into the systemic circulation at therapeutically relevant concentrations. This scenario is especially challenging in the treatment of chronic diseases (such as type 2 diabetes mellitus), wherein daily injections are often needed. However, for certain peptides, there may be an alternative in drug delivery to meet the need for increased peptide bioavailability; this is the case for gut hormone mimetics (including glucagon-like peptide (GLP)-1 or GLP-2). One plausible alternative for improved oral delivery of these peptides is the co-stimulation of the endogenous secretion of the hormone to reach therapeutic levels of the peptide. This oration will be focused on studies conducted on the stimulation of gut hormones secreted from enteroendocrine L cells in the treatment of gastrointestinal disorders, including a critical discussion of the limitations and future perspectives of implementing this approach in the clinical setting. [Display omitted] [ABSTRACT FROM AUTHOR]

Many individuals with autism spectrum disorder (ASD) experience various degrees of impairment in social interaction and communication, restricted, repetitive behaviours, interests/activities. These impairments make a significant contribution to poorer everyday adaptive functioning. Yet, there are no pharmacological therapies to effectively treat the core symptoms of ASD. Since symptoms of ASD likely emerge from a complex interplay of vulnerabilities, environmental factors and compensatory mechanisms during the early developmental period, pharmacological interventions arguably would have the greatest impact to improve long-term outcomes when implemented at a young age. It is essential therefore, that clinical development programmes of investigational drugs in ASD include the paediatric population early on in clinical trials. Such trials need to offer the prospect of direct benefit (PDB) for participants. In most cases in drug development this prospect is supported by evidence of efficacy in adults. However, the effectiveness of treatment approaches may be age-dependent, so that clinical trials in adults may not provide sufficient evidence for a PDB in children. In this white paper, we consolidate recommendations from regulatory guidelines, as well as advice from the Food and Drug Administration, USA (FDA) and the Committee for Human Medicinal Products (CHMP) consultations on various development programmes on: 1) elements to support a PDB to participants in early paediatric clinical trials in ASD, including single-gene neurodevelopment disorders, 2) aspects of study design to allow for a PDB. This white paper is intended to be complementary to existing regulatory guidelines in guiding industry and academic sponsors in their conduct of early paediatric clinical trials in ASD. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has thrust RNA as a platform for drug development into the spotlight. However, identifying promising drug candidates is challenging. With advances in synthetic biology and artificial intelligence (AI) models, we can overcome this hurdle, transforming drug development and ushering in a new era in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Exploiting a convenient and highly bioavailable ocular drug delivery approach is currently one of the hotspots in the pharmaceutical industry. Eyelid topical application is seen to be a valuable strategy in the treatment of chronic ocular diseases. To further elucidate the feasibility of eyelid topical administration as an alternative route for ocular drug delivery, pharmacokinetic and pharmacodynamic studies of pilocarpine were conducted in rabbits. Besides, a novel physiologically based pharmacokinetic (PBPK) model describing eyelid transdermal absorption and ocular disposition was developed in rabbits. The PBPK model of rabbits was extrapolated to human by integrating the drug-specific permeability parameters and human physiological parameters to predict ocular pharmacokinetic in human. After eyelid topical application of pilocarpine, the concentration of pilocarpine in iris peaked at 2 h with the value of 18,724 ng/g and the concentration in aqueous humor peaked at 1 h with the value of 1,363 ng/mL. Significant miotic effect were observed from 0.5 h to 4.5 h after eyelid topical application of pilocarpine in rabbits, while that were observed from 0.5 h to 3.5 h after eyedrop instillation. The proposed eyelid PBPK model was capable of reasonably predicting ocular exposure of pilocarpine after application on the eyelid skin and based on the PBPK model, the human ocular concentration was predicted to be 10-fold lower than that in rabbits. And it was suggested that drugs applied on the eyelid skin could transfer into the eyeball through corneal pathway and scleral pathway. This work could provide pharmacokinetic and pharmacodynamic data for the development of eyelid drug delivery, as well as the reference for clinical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Organoids are small, self-organizing three-dimensional cell cultures that are derived from stem cells or primary organs. These cultures replicate the complexity of an organ, which cannot be achieved by single-cell culture systems. Organoids can be used in testing of new drugs instead of animals. Development and validation of organoids is thus important to reduce the reliance on animals for drug testing. In this review, we have discussed the developmental and regulatory aspects of organoids and highlighted their importance in drug development. We have first summarized different types of culture-based organoid systems such as submerged Matrigel, micro-fluidic 3D cultures, inducible pluripotent stem cells, and air-liquid interface cultures. These systems help us understand the intricate interplay between cells and their surrounding milieu for identifying functions of target receptors, soluble factors, and spatial interactions. Further, we have discussed the advances in humanized severe-combined immunodeficiency mouse models and their applications in the pharmacology of immune-oncology. Since regulatory aspects are important in using organoids for drug development, we have summarized FDA and EMA regulations on organoid research to support pre-clinical studies. Finally, we have included some unique studies highlighting the use of organoids in studying infectious diseases, cancer, and fundamental biology. These studies also exemplify the latest technological advances in organoid development resulting in improved efficiency. Overall, this review comprehensively summarizes the applications of organoids in early drug development during discovery and pre-clinical studies. [ABSTRACT FROM AUTHOR]

[Display omitted] • This is the most systematic review of flavonoid drugs and clinical candidates to date. • 19 flavonoid drugs are approved for the market, while 36 candidates in clinical phases. • 52.6% of the marketed flavonoid drugs and 44.4% of clinical candidates are natural sources. • 30% of the marketed flavonoid drugs are used for the treatment of cardiovascular diseases. • 50% of the suspended clinical candidates are antineoplastic and immunomodulating agents. • Unexpectedly, flavonoid glycosides account for 36.8% of the marketed flavonoid drugs. Flavonoids are one of the most important metabolites with vast structural diversity and a plethora of potential pharmacological applications, which have drawn considerable attention in the laboratory. Nevertheless, it remains uncertain how many candidates were progressed to clinical application. We carried out a critical review of natural and semi-synthetic flavonoid drugs and candidates undergoing different clinical phases worldwide by applying an adequate search method and conducted a brief cheminformatic and bioinformatic analysis. It was expected that the obtained results might narrow the screening scope and reduce the cost of drug research and development. To our knowledge, this is the most systematic summarization of flavonoid-based drugs and clinical candidates to date. It was found that a total of 19 flavonoid-based drugs have been approved for the market, and of these, natural flavonoids accounted for 52.6%. Besides, a total of 36 flavonoid-based clinical candidates are undergoing or suspended in different phases, and of these, natural flavonoids account for 44.4%. Thus, natural flavonoids remain the best option for finding novel agents/active templates, and when investigated in conjunction with synthetic chemicals and biologicals, they offer the potential to discover novel structures that can lead to effective agents against a variety of human diseases. Additionally, flavonoid-based marketed drugs have been successful in cardiovascular treatment, and the related drugs account for more than 30% of marketed drugs. However, the use of flavonoids as antineoplastic and immunomodulating agents is not likely for approximately 50% of the candidates suspended in the clinical stage. Interestingly, the marketed drugs covered a broader range of chemical spaces based on size, polarity, and three-dimensional structure compared to the clinical candidates. In addition, flavonoid glycosides with poor oral bioavailability account for 36.8% of the marketed drugs, and thus, they could be thoroughly investigated. [ABSTRACT FROM AUTHOR]

An integrated platform was developed for NP-inspired PROTAC design, target identification and drug discovery. As a proof-of-concept study, this platform was applied to target characterization of 3-fluoro-10-hydroxylevodiamine, which highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery. [Display omitted] • A new strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of natural products. • The PROTAC-based target identitication strategy was successfully applied to characterize REXO4 as a direct target of 3-fluoro-10-hydroxylevodiamine. • Evodiamine-inspired PROTAC 13c showed potent antitumor activity and reduced toxic side effects through REXO4 degradation. Natural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. Inspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. Taking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. In this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10-hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo , leading to potent antitumor activities and reduced toxic side effects. In summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development. [ABSTRACT FROM AUTHOR]

Small nucleic acid drugs, composed of nucleotides, represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics. These agents function by selectively targeting specific genes or their corresponding messenger RNAs (mRNAs), further modulating gene expression and regulating translation-related processes. Prominent examples within this category include antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), microRNAs (miRNAs), and aptamers. The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity, facile design, abbreviated development cycles, expansive target spectrum, and prolonged activity. Overcoming challenges such as poor stability, immunogenicity, and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems. This review provides an overview of the current status and prospective trends in small nucleic acid drug development. Commencing with a historical context, we introduce the primary classifications and mechanisms of small nucleic acid drugs. Subsequently, we delve into the advantages of the U.S. Food and Drug Administration (FDA) approved drugs and mainly discuss the challenges encountered during their development. Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues, promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development. Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs. This review provides an overview of the current status and prospective trends in small nucleic acid drug development, including the development history, drug classifications, and mechanisms, and mainly discusses the advantages of these drugs and the challenges encountered during their development. [Display omitted] [ABSTRACT FROM AUTHOR]

Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium – Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market. [ABSTRACT FROM AUTHOR]

Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs. [ABSTRACT FROM AUTHOR]

The evolution of antimicrobial resistance (AMR), driven by the misuse of drugs – but also by the rationale with which antimicrobials are currently used – is a global health problem. The main measures against AMR are the prudent use of antimicrobials, rapid diagnostics, and the development of new drugs. Forecasting the evolution of AMR, we argue, could add to the arsenal of measures to control and reduce the spread of AMR. While many examples of forecasting or prediction are scattered throughout the literature, it is not yet seriously considered for addressing AMR. Forecasting, while challenging, will contribute to the sustainable use of antimicrobials and hence make them economically more viable. It will also inform the treatment of persistent infections. Operationalizing the forecasting of evolving resistance will provide an additional tool to combat the spread of AMR; it will require the development of bespoke technology, adapted computational approaches, stakeholder involvement, and a shift in mindset from a posteriori to a priori measures. Antimicrobial resistance (AMR) is a major global health issue. Current measures for tackling it comprise mainly the prudent use of drugs, the development of new drugs, and rapid diagnostics. Relatively little attention has been given to forecasting the evolution of resistance. Here, we argue that forecasting has the potential to be a great asset in our arsenal of measures to tackle AMR. We argue that, if successfully implemented, forecasting resistance will help to resolve the antibiotic crisis in three ways: it will (i) guide a more sustainable use (and therefore lifespan) of antibiotics and incentivize investment in drug development, (ii) reduce the spread of AMR genes and pathogenic microbes in the environment and between patients, and (iii) allow more efficient treatment of persistent infections, reducing the continued evolution of resistance. We identify two important challenges that need to be addressed for the successful establishment of forecasting: (i) the development of bespoke technology that allows stakeholders to empirically assess the risks of resistance evolving during the process of drug development and therapeutic/preventive use, and (ii) the transformative shift in mindset from the current praxis of mostly addressing the problem of antibiotic resistance a posteriori to a concept of a priori estimating, and acting on, the risks of resistance. [ABSTRACT FROM AUTHOR]

Phenotypic screens still produce novel drug discoveries, even though the emergence of the finer molecular details of cancer favors target-focused approaches. Recent efforts to improve the design and power of phenotypic screens have addressed the persistent shortcomings of target-focused discovery, such as those related to heterogeneity, resistance, or redundancy. Innovations in culturing patient-derived cancer cells in a tumor-relevant microenvironment have improved the disease relevance of findings. Technological advances for high-throughput screening, ranging from imaging to omics, have increased the information content of readouts and strengthened discovery by phenotype-focused approaches. Before molecular pathways in cancer were known to a depth that could predict targets, drug development relied on phenotypic screening, where the effectiveness of candidate chemicals is judged from functional readouts without considering the mechanisms of action. The unraveling of tumor-specific pathways has brought targets for molecularly driven drug discovery, but precedents in the field have shown that awareness of pathways does not necessarily predict therapeutic efficacy, and many cancers still lack druggable targets. Phenotypic screening therefore retains a niche in drug development where a targeted approach is not informative. We analyze the unique advantages of phenotypic screens, and how technological advances have improved their discovery power. Notable advances include the use of larger biological panels and refined protocols that address the disease-relevance and increase data content with imaging and omic approaches. [ABSTRACT FROM AUTHOR]

Recent advancements have highlighted the crucial role of G-protein-coupled receptors (GPCRs) in dermal injuries, chronic inflammatory dermatoses, and cutaneous malignancies, revealing new therapeutic targets. Targeting transient receptor potential (TRP) channel proteins and GPCR complexes enables the regulation of calcium ion influx, which in turn modulates inflammatory responses in the skin. The utilization of cryo-electron microscopy has significantly advanced our understanding of GPCR structures and molecular binding mechanisms in skin diseases. Advances in understanding GPCR regulation in the development of skin diseases unveil therapeutic possibilities. Achieving the efficacy and specificity of G-protein-coupled receptor (GPCR) targeting-drugs in the skin remains challenging. Understanding the molecular mechanism underlying GPCR dysfunction is crucial for developing targeted therapies. Recent advances in genetic, signal transduction, and structural studies have significantly improved our understanding of cutaneous GPCR functions in both normal and pathological states. In this review, we summarize recent discoveries of pathogenic GPCRs in dermal injuries, chronic inflammatory dermatoses, cutaneous malignancies, as well as the development of potent potential drugs. We also discuss targeting of cutaneous GPCR complexes via the transient receptor potential (TRP) channel and structure elucidation, which provide new opportunities for therapeutic targeting of GPCRs involved in skin disorders. These insights are expected to lead to more effective and specific treatments for various skin conditions. [ABSTRACT FROM AUTHOR]

Magnesium (Mg2+) is an abundant cation in the human body, with important biological effects. Despite its widely acknowledged roles in human health, the optimal approach to assess Mg2+ status is subject to debate. Adequate dietary Mg2+ intake and/or Mg2+ supplementation has potential beneficial effects for preventing and treating diseases affecting many organ systems; however, its effects in most diseases remain controversial because of limited evidence. Although several mechanisms have been proposed for the medical effects of Mg2+, the exact mechanisms for its efficacy remain unknown in most diseases. Elucidation of the mechanisms of action of Mg2+ could guide novel drug development for tissue-specific treatments without systemic side effects. Magnesium (Mg2+) is a commonly used dietary supplement for the prevention and treatment of diseases. However, the efficacy and mechanisms of action of Mg2+ in most diseases have been controversial because of conflicting findings in earlier studies. Recent clinical and preclinical studies provide novel insights into the use of Mg2+ for the treatment and prevention of diseases affecting different organ systems. In this review, we provide an overview of recent clinical evidence for, and controversies over, the medical benefits of Mg2+. In addition, we critically discuss recent advances in understanding the mechanisms of action of Mg2+, which could enable the development of novel targeted therapies. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphorylation is a post-translational modification that regulates protein structure to modulate demic organisms' homeostasis and function. This physiological process is regulated by two enzyme families, protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). As an important regulator of protein function, PTPs are indispensable for maintaining cell intrinsic physiology in different systems, as well as liver physiological and pathological processes. Dysregulation of PTPs has been implicated in multiple liver-related diseases, including chronic liver diseases (CLDs), hepatocellular carcinoma (HCC), and liver injury, and several PTPs are being studied as drug therapeutic targets. Therefore, given the regulatory role of PTPs in diverse liver diseases, a collated review of their function and mechanism is necessary. Moreover, based on the current research status of targeted therapy, we emphasize the inclusion of several PTP members that are clinically significant in the development and progression of liver diseases. As an emerging breakthrough direction in the treatment of liver diseases, this review summarizes the research status of PTP-targeting compounds in liver diseases to illustrate their potential in clinical treatment. Overall, this review aims to support the development of novel PTP-based treatment pathways for liver diseases. Protein tyrosine phosphatases are involved in liver disease progression by catalyzing substrates dephosphorylation and some of them are potential therapeutic targets. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease globally. It initiates with simple steatosis (NAFL) and can progress to the more severe condition of non-alcoholic steatohepatitis (NASH). NASH often advances to end-stage liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Notably, the transition from NASH to end-stage liver diseases is irreversible, and the precise mechanisms driving this progression are not yet fully understood. Consequently, there is a critical need for the development of effective therapies to arrest or reverse this progression. This review provides a comprehensive overview of the pathogenesis of NASH, examines the current therapeutic targets and pharmacological treatments, and offers insights for future drug discovery and development strategies for NASH therapy. [ABSTRACT FROM AUTHOR]

Significant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients. We outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages). By analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies. The field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients. [ABSTRACT FROM AUTHOR]

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs. An advanced framework for drug safety assessment, encompassing precise drug off-target profile prediction and its utilization in ATC classification, toxicity prediction, and ADR enrichment analysis. [Display omitted] [ABSTRACT FROM AUTHOR]

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1 -overexpression (Prdx1 -OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l -Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC 0‒ t , half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI. Marine-derived S14 targets PRDX1 and regulates PRDX1/Nrf2 to mitigate AKI-induced reactive oxygen species. A S14-loaded Kim-1-targeted nanodelivery system was established to enhance renal biodistribution and pharmacokinetics properties for AKI therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic mental illness that affects up to 1% of the population. While efficacious therapies are available for positive symptoms, effective treatment of cognitive and negative symptoms remains an unmet need after decades of research. New developments in the field of neuroimaging are accelerating our knowledge gain regarding the underlying pathophysiology of symptoms in schizophrenia and psychosis spectrum disorders, inspiring new targets for drug development. However, no validated and qualified biomarkers are currently available to support the development of new therapeutics. This review summarizes the current use of neuroimaging technology in clinical drug development for psychotic disorders. As exemplified by drug development programs that target NMDA receptor hypofunction, neuroimaging results play a critical role in target discovery and establishing target engagement and dose selection. Furthermore, pharmacological neuroimaging may provide response biomarkers that allow for early decision making in proof-of-concept studies that leverage pharmacological challenge models in healthy volunteers. That said, while response and predictive biomarkers are starting to be evaluated in patient populations, they continue to play a limited role. Novel approaches to neuroimaging data acquisition and analysis may aid the establishment of biomarkers that are predictive at the individual level in the future. Nevertheless, various gaps in knowledge need to be addressed and biomarkers need to be validated to establish them as "fit for purpose" in drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] • A human iPSCs-based high-throughput anti-seizure compounds screening platform was built. • The human iPSCs-derived neurons can effectively and efficiently predict positive compounds. • This integrated anti-seizure drug discovering approach combines the advantages of human genetic background, HTS, and animal brain network. • Piperine, magnolol, α-asarone, and osthole can reduce epileptiform activity and seizures. • Natural compounds are promising candidates used for anti-seizure drug discovery. One-third of people with epilepsy continue to experience seizures despite treatment with existing anti-seizure medications (ASMs). The failure of modern ASMs to substantially improve epilepsy prognosis has been partly attributed to overreliance on acute rodent models in preclinical drug development as they do not adequately recapitulate the mechanisms of human epilepsy, are labor-intensive and unsuitable for high-throughput screening (HTS). There is an urgent need to find human-relevant HTS models in preclinical drug development to identify novel anti-seizure compounds. This paper developed high-throughput preclinical screening models to identify new ASMs. 14 natural compounds (α-asarone, curcumin, vinpocetine, magnolol, ligustrazine, osthole, tanshinone IIA, piperine, gastrodin, quercetin, berberine, chrysin, schizandrin A and resveratrol) were assessed for their ability to suppress epileptiform activity as measured by multi-electrode arrays (MEA) in neural cultures derived from human induced pluripotent stem cells (iPSCs). In parallel, they were tested for anti-seizure effects in zebrafish and mouse models, which have been widely used in development of modern ASMs. The effects of the compounds in these models were compared. Two approved ASMs were used as positive controls. Epileptiform activity could be induced in iPSCs-derived neurons following treatment with 4-aminopyridine (4-AP) and inhibited by standard ASMs, carbamazepine, and phenytoin. Eight of the 14 natural compounds significantly inhibited the epileptiform activity in iPSCs-derived neurons. Among them, piperine, magnolol, α-asarone, and osthole showed significant anti-seizure effects both in zebrafish and mice. Comparative analysis showed that compounds ineffective in the iPSCs-derived neural model also showed no anti-seizure effects in the zebrafish or mouse models. Our findings support the use of iPSCs-derived human neurons for first-line high-throughput screening to identify compounds with anti-seizure properties and exclude ineffective compounds. Effective compounds may then be selected for animal evaluation before clinical testing. This integrated approach may improve the efficiency of developing novel ASMs. [ABSTRACT FROM AUTHOR]

Liver diseases pose significant challenges to global public health. In the realm of drug discovery and development, overcoming 'on-target off-tissue' effects remains a substantial barrier for various diseases. In this study, we have pioneered a Liver-Targeting Chimera (LIVTAC) approach using a proteolysis-targeting chimera (PROTAC) molecule coupled to the liver-specific asialoglycoprotein receptor (ASGPR) through an innovative linker attachment strategy for the precise induction of target protein degradation within the liver. As a proof-of-concept study, we designed XZ1606, a mammalian bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent, which not only demonstrated enduring tumor suppression (over 2 months) in combination with sorafenib but also an improved safety profile, notably ameliorating the incidence of thrombocytopenia, a common and severe on-target dose-limiting toxic effect associated with conventional BET inhibitors. These encouraging results highlight the potential of LIVTAC as a versatile platform for addressing a broad spectrum of liver diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112). Following 2020 PRISMA guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified 'Toxicological Data Reliability Assessment Tool'. A total of 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no consensus on drug concentrations. Extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative control drugs for validation of in vitro models of DILI is proposed. Prediction of human toxicity early in the drug development process remains a major challenge, necessitating the development of more physiologically relevant liver models and careful selection of drug-induced liver injury (DILI)-positive and -negative control drugs to better predict the risk of DILI associated with new drug candidates. Thus, this systematic study has crucial implications for standardizing the validation of new in vitro models of DILI. By establishing a consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approach to drug safety assessment. [Display omitted] • Identification of DILI during preclinical stages remains challenging, underscoring the need for appropriate test drugs. • Through a systematic review, the article analyzes compounds used in in vitro hepatotoxicity assays. • A list of 20 control drugs, supported by literature, clinical data and an expert committee was created. • The consensus-driven list aims to enhance the validation and standardization of in vitro models. [ABSTRACT FROM AUTHOR]

Medicinal plants are enriched sources of drugs due to their chemically and functionally diverse secondary metabolites. Conventional methods of screening these bioactive metabolites require a long time, incur high costs, utilize substantial amounts of solvents, involve repeated exposure to heat (harmful for the thermo-labile compounds), and often lead to undesirable products. However, computer-aided drug discovery (CADD) has emerged as a versatile and cost-effective tool for expediting the screening of plant-based bioactive compounds. In this review, we focus on structure-based and ligand-based drug discovery approaches and their roles in rationalizing drug development. We discuss the technicalities, limitations, and successful applications of key components of structure-based (molecular docking and molecular dynamics) and ligand-based (quantitative structure–activity relationship and pharmacophore modeling) approaches in medicinal plant-derived drug discovery. Furthermore, our study highlights the significance of the pharmacokinetic and ADMET profiling of plant-based therapeutics in drug development. Besides the applications of computational drug discovery, we also briefly overview the corroborative in-silico and experimental approaches to identify potential therapeutics from medicinal plants. This study suggests that integrating advanced Machine Learning and Artificial Intelligence approaches could alleviate the challenges faced by traditional computational techniques, thus enriching the screening process. [Display omitted] • The screening of therapeutic phytochemicals remains challenging. • Computational approaches can expedite drug discovery from medicinal plants. • Structure- and ligand-based modeling are vital pillars of in-silico drug discovery. • Early-stage ADME-Tox analysis of phytocompounds aids the discovery of potent drug. • Combined in-silico and in-vitro studies can validate the drug discovery results. [ABSTRACT FROM AUTHOR]

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets. Among them, targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells. This new form of drug development includes various types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera (AUTAC), autophagy-targeting chimera (AUTOTAC), degrader-antibody conjugate (DAC). This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets. Finally, the article looks forward to the future development direction and application prospects of targeted protein degradation technology. [ABSTRACT FROM AUTHOR]

Various tests based on different biomarkers have been developed to identify the best candidates for poly(ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine. Various tests based on different biomarkers have been developed to identify the best candidates for poly (ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine. [ABSTRACT FROM AUTHOR]

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research. [ABSTRACT FROM AUTHOR]

The oncoprotein MYC has been considered 'undruggable' but increasingly direct and indirect methods of targeting are being identified and some compounds are showing strong pharmacological effects. However, responses to indirect targets have lacked efficacy and durability. Combination therapies targeting MYC are being examined with anti-MYC drugs in combination with approved drugs progressing to clinical studies. Combinations co-targeting MYC show strong effects in pre-clinical studies. Dual inhibitors of MYC targets offer the same promise, but with simplified treatment regimens and possibly enhance efficacy compared with combinations. The pharmacokinetics of combinations and dual inhibitors provides an important additional challenge that needs to be addressed in the development of new treatments. Members of the MYC family of proteins are a major target for cancer drug discovery, but the development of drugs that block MYC-driven cancers has not yet been successful. Approaches to achieve success may include the development of combination therapies or dual-acting drugs that target MYC at multiple nodes. Such treatments hold the possibility of additive or synergistic activity, potentially reducing side effect profiles and the emergence of resistance. In this review, we examine the prominent MYC-related targets and highlight those that have been targeted in combination and/or dual-target approaches. Finally, we explore the challenges of combination and dual-target approaches from a drug development perspective. [ABSTRACT FROM AUTHOR]

[Display omitted] • HIGD1A and ZG16, lower expressed in COAD than in READ, are both associated with poor prognosis in COAD, but not in READ. • Compared with ZG16, HIGD1A showed more efficiency in suppressing tumor growth and metastasis in CRC cells. • miR-501-3p, higher expressed in COAD than in READ, promoted CRC cells proliferation, invasion, and migration through suppressing HIGD1A expression. • High leveled miR-501-3p inhibited HIGD1A expression in COAD, which promoted tumor growth and metastasis, and eventually caused poor prognosis in COAD. • Procyanidin C1 (PCC1), a kind of natural polyphenol has been verified as a potential miR-501-3p inhibitor, which modulated miR-501-3p/HIGD1A axis and inhibited tumor growth and metastasis in vivo and in vitro. Although colon (COAD) and rectal adenocarcinoma (READ) combined to refer to colorectal cancer (CRC), substantial clinical evidence urged that CRC should be treated as two different cancers due to compared with READ, COAD showed higher morbidity and worse 5-year survival. This study has tried to screen for the crucial gene that caused the worse prognosis and investigate its mechanism for mediating tumor growth and metastases in COAD. Meanwhile, the potential anti-COAD compound implicated in this mechanism was identified and testified from 1,855 food-borne chemical kits. This study aims to bring a new perspective to the development of new anti-COAD drugs and personalized medicine for patients with COAD. The survival-related hub genes in COAD and READ were screened out from The Cancer Genome Atlas (TCGA) database and the results showed that HIGD1A , lower expressed in COAD than in READ, was associated with poor prognosis in COAD patients, but not in READ. Over-expressed HIGD1A suppressed CRC cell proliferation, invasion, and migration in vitro and in vivo. Meanwhile, the different expressed microRNA profiles between COAD and READ showed that miR-501-3p was highly expressed in COAD and inhibited HIGD1A expression by targeting 3′UTR of HIGD1A. MiR-501-3p mimics promoted cell proliferation and metastasis in CRC cells. In addition, Procyanidin C1 (PCC1), a kind of natural polyphenol has been verified as a potential miR-501-3p inhibitor. In vitro and in vivo , PCC1 promoted HIGD1A expression by suppressing miR-501-3p and resulted in inhibited tumor growth and metastasis. The present study verified that miR-501-3p/HIGD1A axis mediated tumor growth and metastasis in COAD. PCC1, a flavonoid that riched in food exerts anti-COAD effects by inhibiting miR-501-3p and results in the latter losing the ability to suppress HIGD1A expression. Subsequently, unfettered HIGD1A inhibited tumor growth and metastasis in COAD. [ABSTRACT FROM AUTHOR]

• The work showed the promising capabilities of the transformer model in capturing the longitudinal PK/PD relationships. • The work provides a systematic exploration and comparison of the currently published NLP models in this field. • Findings in these cutting-edge machine learning approaches are anticipated to streamline future drug development. There remains a substantial need for a comprehensive assessment of various natural language processing (NLP) algorithms in longitudinal pharmacokinetic/pharmacodynamic (PK/PD) modeling despite recent advances in machine learning in the space of quantitative pharmacology. We herein investigated the application of the transformer model and further compared the performance among several different NLP models, including long short-term memory (LSTM) and neural-ODE (Ordinary Differential Equation) in analyzing longitudinal PK/PD data using virtual data containing three different regimens. Results suggested that LSTM and neural-ODE, along with their respective variants provide a strong performance when predicting from training-included (seen) regimens, albeit with slight information loss for training-excluded (unseen) regimens. Similarly, as with neural-ODE, the transformer exhibited superior performance in describing time-series PK/PD data. Nonetheless, when extrapolating to unseen regimens, while outlining the general data trends, it encountered difficulties in precisely capturing data fluctuations. Remarkably, a small integration of unseen data into the training dataset significantly bolsters predictive performance for both seen and unseen regimens. Our study marks a pioneering effort in deploying the transformer model for time-series PK/PD analysis and provides a systematic exploration of the currently available NLP models in this field. [ABSTRACT FROM AUTHOR]

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e. , the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development. [ABSTRACT FROM AUTHOR]

The dimer of the neuronal receptor tyrosine kinase-2 (TrkB) transmembrane domains (TMDs) is a novel target for drug binding. Antidepressant drugs act as allosteric potentiators of brain-derived neurotrophic factor (BDNF) signaling through binding to TrkB. Cholesterol modulates the structure and function of TrkB. Agonist TrkB antibodies are being developed for neurodegenerative disorders. TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the receptor for brain-derived neurotrophic factor (BDNF) and is a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding of the structure and function of TrkB, including its transmembrane domain (TMD). TrkB interacts with membrane cholesterol, which bidirectionally regulates TrkB signaling. Additionally, TrkB has recently been recognized as a binding target of antidepressant drugs. A variety of different antidepressants, including typical and rapid-acting antidepressants, as well as psychedelic compounds, act as allosteric potentiators of BDNF signaling through TrkB. This suggests that TrkB is the common target of different antidepressant compounds. Although more research is needed, current knowledge suggests that TrkB is a promising target for further drug development. [ABSTRACT FROM AUTHOR]

In a typical tablet or capsule formulation, the active drug is often present as a crystalline solid. This solid emerges from the relationships between the individual atoms within the crystal, which confer a distinct set of physical properties. Then, it follows that if we modify the packing arrangement of the individual molecules within these crystals, we can modulate their properties. This can be achieved by crystal engineering. Crystal engineering has also seen teams arrange multiple drug molecules within the same crystal, resulting in dramatic improvements to drug properties in the lab. The success of drugs like SEGLENTIS® and Entresto® have revitalised interest in these forms, but controversy surrounding their translation has prompted this reconsideration of their clinical utility. I reflect on the current academic, clinical, and commercial interest in multidrug multicomponent crystals, drawing parallels with developments pre-Bragg, contributing to a nuanced understanding of the potential and limitations of crystal engineering in pharmaceutical applications. [Display omitted] • Blockbuster medicines has initiated a growing interest in these forms. • A growing number of literature reports postulate novel clinical impacts. • No author has demonstrated the superiority of their novel form. • Unusual clinical trial methods for Entresto® and now SEGLENTIS® are highlighted. [ABSTRACT FROM AUTHOR]

Protein phosphatase 2A (PP2A) is an essential serine/threonine protein phosphatase, and its dysfunction is involved in the onset of cancer and neurodegenerative disorders. PP2A functions as a trimeric holoenzyme whose composition is regulated by the methyl-esterification (methylation) of the PP2A catalytic subunit (PP2Ac). Protein phosphatase methylesterase-1 (PME-1) is the sole PP2Ac methylesterase, and the higher PME-1 expression is observed in various cancer and neurodegenerative diseases. Apart from serving as a methylesterase, PME-1 acts as a PP2A inhibitory protein, binding directly to PP2Ac and suppressing its activity. The intricate function of PME-1 hinders drug development by targeting the PME-1/PP2Ac axis. This study applied the NanoBiT system, a bioluminescence-based protein interaction assay, to elucidate the molecular mechanism that modulates unknown PME-1/PP2Ac protein–protein interaction (PPI). Compound screening identified that the CHK1 inhibitors inhibited PME-1/PP2Ac association without affecting PP2Ac methylation levels. CHK1 directly phosphorylates PP2Ac to promote PME-1 association. Phospho-mass spectrometry identified multiple phospho-sites on PP2Ac, including the Thr219, that affect PME-1 interaction. An anti-phosphoThr219 PP2Ac antibody was generated and showed that CHK1 regulates the phosphorylation levels of this site in cells. On the contrary, in vitro phosphatase assay showed that CHK1 is the substrate of PP2A, and PME-1 hindered PP2A-mediated dephosphorylation of CHK1. Our data provides novel insights into the molecular mechanisms governing the PME-1/PP2Ac PPI and the triad relationship between PP2A, PME-1, and CHK1. [ABSTRACT FROM AUTHOR]

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development. However, it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors (TFs) except for the nuclear receptor family of TFs. Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma (GEA) or the therapeutic effects of targeting TF and transcription cofactor complexes. In this study, we found that ETS homologous factor (EHF) expression is promoted by a core transcriptional regulatory circuitry (CRC), specifically ELF3-KLF5-GATA6, and interference with its expression suppressed the malignant biological behavior of GEA cells. Importantly, we identified Ajuba LIM protein (AJUBA) as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA. Furthermore, we identified KRAS signaling as a common pathway downstream of EHF and AJUBA. Applicably, dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo. In conclusion, EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway. Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy. EHF is upregulated by a core transcriptional regulatory circuitry and promotes malignancy of gastroesophageal adenocarcinoma via AJUBA coactivation through the KRAS pathway, offering a novel dual-targeting therapeutic strategy. [Display omitted] [ABSTRACT FROM AUTHOR]

Drug transporters are essential players in the transmembrane transport of a wide variety of clinical drugs. The broad substrate spectra and versatile distribution pattern of these membrane proteins infer their pharmacological and clinical significance. With our accumulating knowledge on the three-dimensional structure of drug transporters, their oligomerization status has become a topic of intense study due to the possible functional roles carried out by such kind of post-translational modification (PTM). In-depth studies of oligomeric complexes formed among drug transporters as well as their interactions with other regulatory proteins can help us better understand the regulatory mechanisms of these membrane proteins, provide clues for the development of novel drugs, and improve the therapeutic efficacy. In this review, we describe different oligomerization forms as well as their structural basis of major drug transporters in the ATP-binding cassette and solute carrier superfamilies, summarize our current knowledge on the influence of oligomerization for protein expression level and transport function of these membrane proteins, and discuss the regulatory mechanisms of oligomerization. Finally, we highlight the challenges associated with the current oligomerization studies and propose some thoughts on the pharmaceutical application of this important drug transporter PTM. As transmembrane proteins, drug transporters are prone to form oligomers. Oligomeric complexes formed among drug transporters or with other regulatory proteins may play important roles in transporter function and expression. [Display omitted] [ABSTRACT FROM AUTHOR]

The Orphan Drug Act (ODA) incentivizes drug development for rare diseases with limited sales potential. Partial orphans—drugs used to treat rare and common diseases—frequently turn into multi-billion dollar blockbusters. This study analyzes partial orphan cancer drugs' development, approval, and economics. 170 drugs with US Food and Drug Administration approval for 455 cancer indications were identified (2000-2021). 110 full, 22 partial, and 38 non-orphan drugs were compared regarding their approval, benefits, trials, epidemiology, price, beneficiaries, and spending with data from regulatory documents, Global Burden of Disease study, and Medicare and Medicaid. Full orphans, relative to partial and non-orphans, were more frequently monotherapies for hematologic cancers supported by smaller single-arm trials treating diseases with a lower incidence and higher severity. The time from first to second indication approval was 1 year shorter for partial than full orphans. Full orphans offered a greater overall survival (median: 4.0 vs 2.8 vs 2.8 months, P <.001) and progression-free survival benefit (median: 5.1 vs 2.5 vs 3.6 months, P <.001). Monthly prices were higher for full and partial than non-orphan drugs (median: $17 177 vs $13 284 vs $12 457, P <.001). Beneficiaries (8790 vs 4390 vs 1730) and spending ($570 vs $305 vs $156 million) per drug were greater for partial than non-and full orphans. Although partial orphans' benefits, trials, and economics are more similar to non-than full orphans, they receive all of the ODA's benefits and are swiftly extended to new indications; resulting in greater spending. A maximum ODA revenue/patient threshold could limit expenditure on partial orphans. • The Orphan Drug Act (ODA) incentivizes drug development for rare diseases with limited sales potential. However, orphan drugs frequently turn into multi-billion dollar blockbusters, particularly those used to treat rare and common diseases: "partial orphans." • This is the first study to analyze the development, US Food and Drug Administration approval, epidemiology, and economics of full, partial, and non-orphan cancer drugs. • We show that the clinical benefit, trials, and epidemiology of partial orphan cancer drugs are more similar to non-orphans than full orphans. • However, partial orphans receive all of the ODA's incentives and are swiftly extended to new indications; resulting in greater prices, beneficiaries, and gross spending. • Establishing a maximum revenue threshold for the ODA's benefits alongside indication-specific pricing could reduce expenditure on partial orphan drugs. [ABSTRACT FROM AUTHOR]

The ancient and highly conserved oxytocin/vasopressin (OT/VP) signaling system has attracted much attention due to its wide-ranging relevance in health and disease. Its brain functions are of particular interest as a potential gateway for treating social and neuropsychiatric disorders. Drug development is fueled by recent advances in medicinal chemistry, ligand–receptor structures for rational drug design, therapeutic lead discovery from nature, exploration of biased signaling, and efforts to target OT/VP receptor oligomers and clusters. Despite promising advances, challenges persist due to signaling complexity, selectivity concerns, interspecies differences, and intricacies in drug delivery. Peptides will play an important role in overcoming some of these challenges. Several OT/VP receptor agonists and antagonists are in clinical trials, and approved drugs are under investigation for new indications. Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development. Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin–vasopressin (OT-VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT-VP signaling systems in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development. [ABSTRACT FROM AUTHOR]

• This study identified higher serologic levels of ADAMTS12 in patients with Eps. • The study identified ADAMTS12 as a useful biological marker for predicting the occurrence and their recurrence of EPs. • It may provide new ideas for the subsequent development of drugs to treat EPs and prevent their recurrence. Endometrial polyps (EPs) are common gynecological disorders for which no clear etiology has been found. ADAMTS have been associated with a variety of diseases. This study aimed to investigate the potential correlation between serologic levels of ADAMTS 5, 9, and 12 in patients with EPs. A total of 88 patients were categorized into two groups: the EPs group, consisting of recurrent EPs and first occurrence EPs, and a control group. The study compared the general information and serum levels of ADAMTS 5, 9, and 12 between the groups. Regarding the general data, a statistically significant age difference (p < 0.05) was observed, while no significant differences were found in the other variables. After considering age as a confounding factor, the previously observed statistical significance in the differences of ADAMTS5 and 9 between the groups diminished. However, it was found that the concentrations of ADAMTS12 in both the EPs group and the recurrent EPs group were significantly higher compared to the control group and the first occurrence EPs group (p < 0.05). ROC curves were generated to determine the critical values of ADAMTS12 for predicting EPs and recurrent EPs, which were found to be 0.6962 ng/ml (sensitivity: 100 %, specificity: 39.5 %) and 0.8768 ng/ml (sensitivity: 75.0 %, specificity: 76.3 %), respectively. Our findings revealed elevated serologic levels of ADAMTS12 in the EPs group, particularly in the recurrent EPs group. Furthermore, ADAMTS-12 was identified as a valuable biomarker for assisting in the diagnosis and prediction of EPs recurrence. [ABSTRACT FROM AUTHOR]

To analyze the associations between development of age-related macular degeneration (AMD) and regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs). We retrospectively recruited individuals who received ≥28-day prescriptions of aspirin or NA-NSAIDs exclusively between 2008 and 2017 in one tertiary center as regular users. Non-regular users were free from regular use of any anti-inflammatory drugs and were matched to regular users in terms of age, sex, and visit date at a ratio of 1–4:1. The aspirin cohort included 36,771 regular users and 110,808 matched non-regular users, while the NA-NSAID cohort included 59,569 regular users and 179,732 matched non-regular users. Stratified multivariate Cox regression analyses with adjustment for systemic confounding factors were performed for the development of AMD and neovascular AMD. In the aspirin cohort, the adjusted hazard ratios of aspirin use for AMD in the whole cohort, individuals without cardiovascular diseases (CVDs), and those with CVDs were 0.664, 0.618, and 0.702, respectively (P < 0.0001 for all), while those of aspirin use for neovascular AMD were 0.486, 0.313, and 0.584 (P < 0.05 for all), respectively. In the NA-NSAID cohort, regular use of NA-NSAIDs was associated with a decreased risk of AMD (hazard ratio = 0.823, P < 0.0001) and neovascular AMD (hazard ratio = 0.720, P = 0.040) only in people without arthritis. Regular use of aspirin or NA-NSAIDs had protective effects on AMD and neovascular AMD. The effect of aspirin was observed in all patients, while the effect of NA-NSAIDs was observed only in people without arthritis. [ABSTRACT FROM AUTHOR]

In this issue of Structure , Chi et al. 1 report structural and functional studies that reveal the inhibition mechanism of the lysosomal two-pore channel TPC2 by the antagonist SG-094, which is of interest for drug development. Antagonist binding induces the downward displacement of the voltage-sensor domain II (VSD II), which is accompanied by asymmetric conformational rearrangements of the entire channel. In this issue of Structure , Chi et al. report structural and functional studies that reveal the inhibition mechanism of the lysosomal two-pore channel TPC2 by the antagonist SG-094, which is of interest for drug development. Antagonist binding induces the downward displacement of the voltage-sensor domain II (VSD II), which is accompanied by asymmetric conformational rearrangements of the entire channel. [ABSTRACT FROM AUTHOR]

Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle. Historical approaches, such as Quality-by-Design (QbD) experiments, are useful for initial evaluations but can be inefficient and cumbersome to maintain once commercial manufacturing commences. The relatively miniscule data sets accessible in product development – used to predict response to a hypothetical risk of variation – become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on our observations of development and manufacturing, we instead propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. Case studies illustrate how correctly contextualizing such data in formulation and process development can avoid the traps of historical QbD approaches and become valuable for evaluating changes occurring later in the drug product lifecycle. [ABSTRACT FROM AUTHOR]

• Analytical method development and suitability assessments with pre-defined acceptance criteria in accordance with regulatory and ICH guidelines were completed for protein concentration, size and charge variants and relative binding to support low concentration and low dose in-use studies. • The developed methods are reliable, well-documented and indicate potential platform use with a variety of mAbs and proteins for in-use studies. • Method modifications and sample matrices do not significantly affect reported results, ensuring these methods can be used across a wide range of protein concentrations. The emergence of highly potent therapeutics with low expected clinical doses creates a challenge for analytical characterization of simulated drug product in-use samples. The low expected protein concentration (often µg/mL) and highly charged and sub-optimal sample matrices like 0.9% saline or 5% dextrose make ensuring dose solution stability and characterizing product quality changes difficult. Health authority expectations require analysis of low concentration in-use samples to be completed with suitable assays to ensure little to no changes are occurring during drug product dose preparation and administration, thus ensuring patient safety. However, characterization of these samples for protein concentration, size variants, charge variants and potency often necessitates additional analytical method development to improve sensitivity and compatibility with in-use samples. Here we report the development and qualification of reliable in-use methods to characterize simulated in-use samples to assist during drug product development. [ABSTRACT FROM AUTHOR]

• Confirming that ensitrelvir did not influence coproporphyrin-I (CP-I) concentrations, indicating the absence of OATP1B inhibitory effects. • Demonstrating the utility of a normalization method using pre-dose values to minimize individual variabilities in CP-I concentrations when comparing the CP-I concentrations with different participants. • Proposal of a normalization method for assessing OATP1B inhibitory potential using CP-I in a placebo-controlled first-in-human study. Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans. [Display omitted] [ABSTRACT FROM AUTHOR]

Advanced therapy medicinal products (ATMPs) are becoming the new kid on the block for the treatment of a variety of indications with promising results. Despite the academic contribution to the basic and clinical research of ATMPs, undertaking a full product development process is extraordinarily challenging and demanding for academic institutions. Meeting regulatory requirements is probably the most challenging aspect of academic development, considering the limited experience and resources compared with pharmaceutical companies. This review aims to outline the key aspects to be considered when developing novel ATMPs from an academic perspective, based on the results of our own experience and interaction with the Spanish Agency of Medicines and Medical Devices (AEMPS) and European Medicine Agency (EMA) related to a number of academic ATMP initiatives carried out at our center during the last 5 years. Emphasis is placed on understanding the regulatory requirements during the early phases of the drug development process, particularly for the preparation of a Clinical Trial Application. Academic centers usually lack expertise in product-related documentation (such as the Investigational Medicinal Product Dossier), and therefore, early interaction with regulators is crucial to understand their requirements and receive guidance to comply with them. Insights are shared on managing quality, nonclinical, clinical, and risk and benefit documentation, based on our own experience and challenges. This review aims to empower academic and clinical settings by providing crucial regulatory knowledge to smooth the regulatory journey of ATMPs. [ABSTRACT FROM AUTHOR]

Targeting translational factor proteins (TFPs) presents significant promise for the development of innovative antitubercular drugs. Previous insights from antibiotic binding mechanisms and recently solved 3D crystal structures of Mycobacterium tuberculosis (Mtb) elongation factor thermo unstable–GDP (EF-Tu–GDP), elongation factor thermo stable–EF-Tu (EF-Ts–EF-Tu), and elongation factor G–GDP (EF-G–GDP) have opened up new avenues for the design and development of potent antituberculosis (anti-TB) therapies. [ABSTRACT FROM AUTHOR]

Intracellular pathogens such as Mycobacterium tuberculosis (Mtb) can evade the immune system and proliferate within host cells, making antibiotic treatment more challenging and potentially resulting in therapeutic failure and antimicrobial resistance. Antibiotic efficacy is influenced by a range of factors across different spatiotemporal domains: tissue-level barriers and cell-specific responses can limit the pharmacokinetics of the drug; whilst different subcellular compartments and microenvironments can affect the pharmacodynamics of the drug. This challenge is further complicated by the heterogeneity of tissue-level infection sites, host-cell types, and pathogenic cell subpopulations. Further to this, this heterogeneity is dynamic: host cells will adopt different disease states dependent on infection, and the intracellular pathogen can possess a dynamic and facultative lifestyle. Ergo, effective chemotherapy is incredibly complex and requires interdisciplinary investigation across varying spatiotemporal scales. The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular compartments. Therefore, TB chemotherapy requires antibiotics crossing multiple biological membranes to reach distinct subcellular compartments and target these bacterial populations. These compartments are also dynamic, and our understanding of intracellular pharmacokinetics (PK) often represents a challenge for antitubercular drug development. In recent years, the development of high-resolution imaging approaches in the context of host–pathogen interactions has revealed the intracellular distribution of antibiotics at a new level, yielding discoveries with important clinical implications. In this review, we describe the current knowledge regarding cellular PK of antibiotics and the complexity of drug distribution within the context of TB. We also discuss the recent advances in quantitative imaging and highlight their applications for drug development in the context of how intracellular environments and microbial localisation affect TB treatment efficacy. [ABSTRACT FROM AUTHOR]