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Since 2015, concentration–QTc (C–QTc) analysis has been used to exclude the possibility that a drug has a concerning effect on the QTc interval. This has enabled the replacement of the designated thorough QT (TQT) study with serial electrocardiograms (ECGs) in routine clinical pharmacology studies, such as the first‐in‐human (FIH) study. The E14 revision has led to an increased proportion of FIH studies with the added objective of QT evaluation, with the intention of replacing the TQT study. With the more recent revision of the S7B/E14 Q&A document in February 2022, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG (human ether‐a‐go‐go‐related gene) and the non‐rodent in vivo study are conducted according to the described best practices and are negative, the previous requirement that a QTc effect of >10 milliseconds must be excluded in healthy subjects at plasma concentrations 2‐fold above what can be seen in patients can be reduced to covering the concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect of >10 milliseconds can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayedrepolarization, if supported by negative best practices hERG and in vivo studies. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment. [ABSTRACT FROM AUTHOR]

Zuranolone (ZURZUVAE™) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABAA) receptor being developed by Sage Therapeutics and Biogen for the treatment of mood disorders. In August 2023, zuranolone received its first approval in the USA for the treatment of adults with postpartum depression [pending scheduling by the US Drug Enforcement Administration (DEA)]. This article summarizes the milestones in the development of zuranolone leading to this first approval. [ABSTRACT FROM AUTHOR]

To investigate FDA-approved drugs prescribed for unrelated diseases or conditions that promote remission in subjects diagnosed with opioid use disorder (OUD). This was a retrospective observational study utilizing the TriNetX electronic medical record data. Subjects between 18 and 65 years old were included in this study. First, a drug screen was employed to identify medications used for chronic illness that are associated with OUD remission. Based on Fisher's exact test for significance, 28 of 101 medications were selected for further analysis. Positive (buprenorphine/methadone) and negative controls (benazepril) were included in the analysis. Medications were analyzed in the absence and presence of buprenorphine or methadone, two medications used to treat OUD, to identify the likelihood of OUD remission up to one year following the index event. We identify 8 medications (prazosin, propranolol, lithium carbonate, olanzapine, quetiapine, bupropion, citalopram, and escitalopram) that may be useful for increasing remission in OUD in the absence of buprenorphine or methadone. Additionally, our results identify psychiatric medications that when taken alongside buprenorphine and methadone improve remission rates. These results provide medication options that may be useful in treating OUD as well as integrated therapies to treat comorbid mental illness. [ABSTRACT FROM AUTHOR]

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach. [ABSTRACT FROM AUTHOR]

With our better understanding of the pathogenesis of various diseases, more and more drugs and biological products are being tried and tested every day. Roughly, around 40--50 novel drugs get approved by the Food and Drug Administration (FDA) for use in the general population, making it difficult for a physician to keep track of the constant changes in therapy. This article aimed to provide a compilation of all the FDA-approved new drugs for dermatological conditions and new dermatological indications of known drugs in the recent past, especially for dermatology residents and practising dermatologists. A comprehensive analysis, based on the list of new molecular entities approved by the FDA from 2020 to 2023, as well as a thorough English language literature search from 2020 to July 2023 across multiple databases (PubMed, MEDLINE, Springer Nature, Google Scholar and Cochrane) for various keywords (alone and in combination) such as "FDA approved" OR "recent advances in therapy" OR "recent drugs" OR "novel treatment" OR "dermatology," was performed. All data extracted were incorporated into the present compilation. A total of 33 drugs, including newly approved and newly approved indications of previously known drugs, were found. Relevant information about them has been discussed in a tabulated manner. This article provides an at a glance summarised profile of the newly FDA-approved drugs, as available in the existing literature. However, with the astonishing rate of new drugs hitting the market, more and more clinical trials are required to ensure the rational use of these agents. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a chronic condition that causes pain and loss of joint function. While currently recommended intra-articular therapies (e.g. corticosteroids and hyaluronic acid) can alleviate some of the symptoms of osteoarthritis, they are currently unable to alter the course of disease progression, and the duration of symptom relief is generally short-term. New therapies are under evaluation for treatment of osteoarthritis; these aim to reverse the pathological structural changes associated with the disease and provide longer-lasting pain relief. This article summarises recent guideline recommendations for intra-articular therapies and highlights some of the new therapies currently in clinical evaluation. [ABSTRACT FROM AUTHOR]

Over the past 30 years, progress has been made in increasing women's representation in clinical research. However, women continue to be underrepresented in phase I clinical trials—those trials that test the safety and tolerability of investigational drugs, often on healthy individuals. As sex‐based differences in adverse drug reactions are often linked to drug dose, pivotal safety information in phase I trials is often insufficiently—and inequitably—captured for females. Yet there has been little attention to how clinical investigators and those charged with overseeing the ethical conduct of these trials perceive the barriers to women's inclusion in phase I trials. To address this gap, we report on 22 interviews with U.S. phase I investigators and institutional review board (IRB) members. Our findings indicate that although these investigators and IRB members acknowledged the importance of including women in clinical trials, they justified women's exclusion from phase I trials by citing the need to manage their reproductive potential. In particular, we identified four key themes that informants used to warrant women's exclusion from phase I trials: the structure of the drug‐development system itself, fears about risks to potential fetuses, distrust of women to prevent pregnancy, and concerns about risks and burdens to institutions from resulting pregnancies. We argue that these rationales reflect structural and cultural barriers to women's inclusion in clinical research that ultimately fail to respect female research participants as persons, highlighting the need for broad‐based solutions. [ABSTRACT FROM AUTHOR]

Purpose Research pharmacy effort required to safely and compliantly manage investigational products (IP) varies between studies. No validated tool exists in the United States to evaluate these differences in effort. The Vizient Pharmacy Research Committee Investigational Drug Services (IDS) Subcommittee previously developed a systematic complexity scoring tool (CST) through expert consensus to assign a complexity score for pharmacy effort. This project seeks to develop and validate complexity categories based on CST scores. Methods Vizient member institutions in IDS assigned a CST complexity score and a perceived complexity category (low, medium, or high) for study initiation and maintenance. Receiver operating characteristic (ROC) curve analysis defined the best CST score cutoff points for each complexity category. Comparing the CST-assigned to the user-perceived complexity category determined whether the CST-assigned complexity category aligned with practitioner assignment. Results A total of 322 responses were used to determine complexity score categories. The AUC values for study initiation and maintenance were 0.79 (P < 0.001) for the low/medium boundary and 0.80 (P < 0.001) for the medium/high boundary, suggesting the performance of the CST is good. The agreement between CST-assigned and user-perceived complexity categories was 60% for study initiation and 58% for maintenance. The Kendall rank correlation coefficient between the raters and ROC categories was strong, with a value of 0.48 for study initiation and 0.47 for maintenance. Conclusion Development of the CST allows IDS pharmacies to objectively measure the complexity of clinical trials, which is a significant step towards assessing workload and guiding resource allocation. [ABSTRACT FROM AUTHOR]

A new ergostane-type steroid named (22E)-3α,6α,9α-ergosta-7,22-diene-3,6,9-triol (1), along with six known steroids 5α,8α-epidioxy-24-ethyl-cholest-6-en-3β-ol (2), ergosterol-5,8-peroxide (3), cerevisterol (4), isocyathisterol (5), 6β-hydroxystigmast-4-en-3-one (6), 6β-hydroxy-4-campesten-3-one (7), were isolated from the fermented unpolished rice media by Periconia pseudobyssoides K5 (Periconiaceae), an endophytic fungus from medicinal plant Toona sureni (Meliaceae). The fermentation takes at 28 ± 2 °C for 30 days. The structure of new steroid (1) was elucidated by extensive spectroscopic measurements (IR, HR-ESI-TOFMS, and 1D and 2D NMR) analyses. The isolated compounds (1–7) were evaluated for heme polymerization inhibition assay (HPIA). The IC50 HPIA value of 1 is 8.24 ± 0.03 mg/ml. [ABSTRACT FROM AUTHOR]

Master protocols (MPs) are an important addition to the clinical trial repertoire. As defined by the U.S. Food and Drug Administration (FDA), this term means "a protocol designed with multiple sub-studies, which may have different objectives (goals) and involve coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure." This means we now have a unique, scientifically based MP that describes how a clinical trial will be conducted using one or more potential candidate therapies to treat patients in one or more diseases. Patient engagement (PE) is also a critical factor that has been recognized by FDA through its Patient-Focused Drug Development (PFDD) initiative, and by the European Medicines Agency (EMA), which states on its website that it has been actively interacting with patients since the creation of the Agency in 1995. We propose that utilizing these PE principles in MPs can make them more successful for sponsors, providers, and patients. Potential benefits of MPs for patients awaiting treatment can include treatments that better fit a patient's needs; availability of more treatments; and faster access to treatments. These make it possible to develop innovative therapies (especially for rare diseases and/or unique subpopulations, e.g., pediatrics), to minimize untoward side effects through careful dose escalation practices and, by sharing a control arm, to lower the probability of being assigned to a placebo arm for clinical trial participants. This paper is authored by select members of the American Statistical Association (ASA)/DahShu Master Protocol Working Group (MPWG) People and Patient Engagement (PE) Subteam. DahShu is a 501(c)(3) non-profit organization, founded to promote research and education in data science. This manuscript does not include direct feedback from US or non-US regulators, though multiple regulatory-related references are cited to confirm our observation that improving patient engagement is supported by regulators. This manuscript represents the authors' independent perspective on the Master Protocol; it does not represent the official policy or viewpoint of FDA or any other regulatory organization or the views of the authors' employers. The objective of this manuscript is to provide drug developers, contract research organizations (CROs), third party capital investors, patient advocacy groups (PAGs), and biopharmaceutical executives with a better understanding of how including the patient voice throughout MP development and conduct creates more efficient clinical trials. The PE Subteam also plans to publish a Plain Language Summary (PLS) of this publication for clinical trial participants, patients, caregivers, and the public as they seek to understand the risks and benefits of MP clinical trial participation. [ABSTRACT FROM AUTHOR]

A Benefit Risk Assessment Plan (BRAP) describes the assessments planned to determine whether the benefits of an investigational drug outweigh the risks. The plan can have two sections, one with timelines for aligning resources with decision milestones and the other for pre-specifying assessments for decision milestones. Regulatory guidance recommends a proactive planning process over an ad-hoc process. However, very little has been published about proactive plans themselves. This article works through a hypothetical example visualizing a series of assessments across the drug development lifecycle. Based on a regulatory framework, the planning process starts with assessing the medical condition and current treatment options. These early assessments bring out major considerations in assessing the investigational drug. [ABSTRACT FROM AUTHOR]

Background: As the implementation of trastuzumab, several studies have investigated new agents and regimens to treat human epidermal growth factor 2-positive (HER2+) metastatic breast cancer (MBC). However, long-term survival analyses from HER2-targeted therapies are lacking. This is a 20-year follow-up study of a phase II trial that evaluated the activity and safety of docetaxel in combination with carboplatin and trastuzumab (TCH) in patients with HER2+ MBC. Materials and Methods: This is a follow-up of a phase II, single-arm, open-label study. The primary objective was the activity from the combination of TCH in terms of response rate (RR). Secondary objectives included the activity from TCH in terms of response duration (RD), time to progression (TTP), overall survival (OS), and percent one-year survival. Results: Between 11/1999 and 10/2002, 40 women were enrolled. Most patients (67.5%) had visceral metastasis on enrollment. After 2 decades and 3 months from first enrollment, there were 4 (10%) survivors (median follow-up of 3.2 years). The RR for complete response (CR) or partial response (PR) was 72.5%. The RR for CR was 42.5%. RD was 8 months. Median TTP was 10.8 months. Participants achieved a median OS of 39.8 months. Percent one-year survival was 92.5%. Conclusion: A subset of patients (10%) receiving trastuzumab in the metastatic setting have achieved long-term survival beyond 20 years. Long-term survival analyses of HER2-targeted therapies are lacking. This is a 20-year follow-up study of a phase II trial that evaluated the activity and safety of docetaxel in combination with carboplatin and trastuzumab in patients with HER2+ metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small compound library comprising FDA‐approved and investigational drugs. Using a neurotoxicity assay format, both respective neuronal population‐based screening campaigns performed robustly (Z‐factors = 0.7–0.8), although the hit rate for the differentiating neurons (2.8%) was slightly higher than for maturing neurons (1.9%). While the majority of hits were toxic to both neuronal populations, these hits predominantly represented promiscuous drugs. Other drugs were selectively neurotoxic, with receptor tyrosine kinase inhibitors disproportionally represented after confirmation. Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Chemoinformatic analyses confirmed differences in potential drug targets that may be differentially expressed during neuronal development. Subsequent studies demonstrated neuronal expression of AXL, an amuvatinib target, in both neuronal populations. However, functional AXL activity was confirmed only in the maturing neuronal population as determined by AXL phosphorylation in response to GAS6, the cognate ligand of AXL, and concurrent STAT3Y705 phosphorylation. Differentiating neurons were unresponsive to the effects of GAS6 suggesting that the AXL‐STAT3 signaling axis was nonfunctional. Amuvatinib treatment of maturing neuronal cultures significantly reduced pAXL levels. These studies indicate that neuronal developmental states may exhibit unique chemosensitivities and that drugs may have different neuro‐inhibitory effects depending upon the developmental stage of the neuronal population. [ABSTRACT FROM AUTHOR]

Simple Summary: Exposure to radiation during nuclear catastrophes, natural sources such as space travel, or during cancer treatment can lead to central nervous system toxicity. The high sensitivity of neural progenitor cells (NPCs) to radiation poses a significant obstacle to dose escalation for the treatment of brain cancer such as glioblastoma, yet studies suggest that higher (dose-escalated) radiation therapy (RT) could enhance local control. Unfortunately, this is presently infeasible due to the toxicity to neighboring normal tissue; thus, there is a critical need to understand the cellular mechanisms that determine the extent of radiation-induced toxicity in normal NPCs, to develop CNS toxicity radiation counter measures or develop new safe brain cancer chemo–radiation therapy strategies. Radiation therapy (RT) is a crucial treatment modality for central nervous system (CNS) tumors but toxicity to healthy CNS tissues remains a challenge. Additionally, environmental exposure to radiation during nuclear catastrophes or space travel presents a risk of CNS toxicity. However, the underlying mechanisms of radiation-induced CNS toxicity are not fully understood. Neural progenitor cells (NPCs) are highly radiosensitive, resulting in decreased neurogenesis in the hippocampus. This study aimed to characterize a novel platform utilizing rat NPCs cultured as 3D neurospheres (NSps) to screen the safety and efficacy of experimental drugs with and without radiation exposure. The effect of radiation on NSp growth and differentiation was assessed by measuring sphere volume and the expression of neuronal differentiation markers Nestin and GFAP and proliferation marker Ki67. Radiation exposure inhibited NSp growth, decreased proliferation, and increased GFAP expression, indicating astrocytic differentiation. RNA sequencing analysis supported these findings, showing upregulation of Notch, BMP2/4, S100b, and GFAP gene expression during astrogenesis. By recapitulating radiation-induced toxicity and astrocytic differentiation, this single-NSp culture system provides a high-throughput preclinical model for assessing the effects of various radiation modalities and evaluates the safety and efficacy of potential therapeutic interventions in combination with radiation. [ABSTRACT FROM AUTHOR]

Eosinophilic gastrointestinal diseases (EGIDs) are an emerging group of pathological entities characterized by an eosinophil-predominant infiltration of different tracts of the gut in the absence of secondary causes of eosinophilia. According to the specific tract of the gut involved, EGIDs can be classified into eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The epidemiology of EGIDs is evolving rapidly. EoE, once considered a rare disease, now has an incidence and prevalence of 7.7 new cases per 100,000 inhabitants per years and 34.4 cases per 100,000 inhabitants per year, respectively. Fewer data are available regarding non-EoE EGIDs, whose prevalence are estimated to range between 2.1 and 17.6 in 100,000 individuals, depending on age, sex, and ethnicity. Diagnosis requires the presence of suggestive symptoms, endoscopic biopsies showing abnormal values of eosinophils infiltrating the gut, and exclusion of secondary causes of eosinophilia. EoE typically presents with dysphagia and episodes of food bolus impactions, while EoG, EoN, and EoC may all present with abdominal pain and diarrhea, with or without other non-specific symptoms. In addition, although different EGIDs are currently classified as different entities, there may be overlap between different diseases in the same patient. Despite EGIDs being relatively novel pathological entities, the research on possible treatments is rapidly growing. In this regard, several randomized controlled trials are currently ongoing to investigate novel molecules, including ad-hoc steroid formulations, immunosuppressants, and mostly monoclonal antibodies that target the specific molecular mediators of EGIDs. This narrative review provides an up-to-date overview of available and investigational drugs for different EGIDs. [ABSTRACT FROM AUTHOR]

Upper airway cough syndrome (UACS) is a common cause of chronic cough characterized by upper airway symptoms, including nasal discharge and throat discomfort. Empirical treatments for UASC-induced chronic cough, such as first-generation antihistamines, have been used; however, the long-term use of these medicines has adverse effects. Therefore, we evaluate the efficacy, safety, and economic feasibility of Wolbigachul-tang (WBGCT), an herbal medication for UASC-induced chronic cough. This is a randomized, double-blind, active-comparator-controlled, parallel, and exploratory clinical trial. Thirty patients with UASC-induced chronic cough will be recruited and randomly allocated to the WBGCT and control groups in a 1:1 allocation ratio. The investigational medicine will be administered three times per day for 2 weeks (3 g of WBGCT at a time). The primary outcome measure is the cough symptom score measured at screening, before starting the trial, and after 2 and 4 weeks. Secondary outcome measures include the cough visual analog scale, nasal discharge score, questionnaire of clinical symptoms of cough and sputum, Leicester cough questionnaire-Korean version, integrative medicine outcome scale, integrative medicine patient satisfaction scale, and 5-level EuroQol 5-dimensional questionnaire, which will be assessed before starting the trial and after 2 and 4 weeks. This study aims to investigate the efficacy, safety, and economic feasibility of WBGCT in the treatment of chronic cough. Therefore, the results of this trial provide evidence for the application of WBGCT in the treatment of UACS-induced chronic cough. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure–activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs’ mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs. [ABSTRACT FROM AUTHOR]

Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline of agents currently in clinical trials. Most of the target processes identified in the Common Alzheimer's Disease Research Ontology (CADRO) are represented by novel agents in trials. Inflammation and synaptic plasticity/neuroprotection are the CADRO categories with the largest number of novel candidate therapies. Within these categories, there are few overlapping targets among the test agents. Additional categories being evaluated include apolipoprotein E ε 4 (APOE4) effects, lipids and lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics and metabolism, vascular factors, cell death, growth factors and hormones, circadian rhythm, and epigenetic regulators. We highlight current drugs being tested within these categories and their mechanisms. Trials will be informative regarding which targets can be modulated to produce a slowing of clinical decline. Possible therapeutic combinations of agents may be suggested by trial outcomes. Biomarkers are evolving in concert with new targets and novel agents, and biomarker outcomes offer a means of supporting disease modification by the putative treatment. Identification of novel targets and development of corresponding therapeutics offer an important means of advancing new treatments for AD. [ABSTRACT FROM AUTHOR]

Regulatory agencies worldwide expect that clinical pharmacokinetic drug–drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug's safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus® to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development. [ABSTRACT FROM AUTHOR]

Background YF-VAX® (Sanofi, Swiftwater, PA), a live, attenuated vaccine based on the yellow fever (YF) substrain 17D-204, is the only YF vaccine licensed in the USA. Manufacturing disruption of YF-VAX and anticipated depletion of the US supply by mid-2017 led to the importation of another YF vaccine, STAMARIL® (Sanofi, France), into the USA under an expanded access investigational new drug program (EAP) to fulfil the public health need for YF vaccination. As part of this program, Sanofi collected enhanced safety surveillance data following vaccination with STAMARIL. Here, we report the results of the enhanced safety surveillance. Methods STAMARIL vaccine was offered to those aged ≥9 months at high risk of YF. Vaccine recipients (or parents/guardians) were instructed to report suspected adverse reactions, any serious adverse events (SAEs) including adverse events of special interest [AESI] occurring after vaccination regardless of suspected relationship, and any inadvertent exposure in pregnancy or breastfeeding within 14 days of vaccination. The AESIs monitored were anaphylaxis, neurotropic disease (YEL-AND) and viscerotropic disease (YEL-AVD). Results Overall, 627 079 individuals received STAMARIL from May 2017 through June 2021; of these, 1308 (0.2%) reported at least one AE, of which 122 reported at least one SAE. There were seven cases of YEL-AND and three cases of YEL-AVD reported, for reporting rates of 1.1 and 0.5 per 100 000 vaccine recipients, respectively. One vaccine recipient developed an anaphylactic reaction (reporting rate: 0.16 per 100 000). No safety concerns were identified from inadvertent vaccine exposure during pregnancy (41 pregnant women) or potential neonatal exposure via breast milk (four exposed infants). Conclusions This study supports the utility of STAMARIL in the EAP as an alternative solution for the YF vaccine shortage in the USA. SAEs were very rare and consistent with the known safety profile of STAMARIL. [ABSTRACT FROM AUTHOR]

Phase 1 and 2a studies of the first drug in a new pharmacological class to be tested in humans have found that the drug was well‐tolerated in healthy volunteers and inhibited the effects of cannabis in individuals with cannabis use disorder. The drug, AEF0117, is a signaling‐specific inhibitor of the cannabinoid receptor 1 (CB1‐SSi) and appears to reduce cannabis self‐administration without precipitating withdrawal, according to the investigators. Results of the studies were published online June 8, 2023, in Nature Medicine. [ABSTRACT FROM AUTHOR]

Despite significant progress in audiology, there is no definitive treatment option for Ménière disease due to its multifactorial etiology. Current Concepts: The primary treatment goal for Ménière disease is first, to decrease the frequency of symptoms and, second, to minimize the severity of vertigo and hearing loss. Concurrently, the preservation of vestibular and auditory functions should be prioritized. The protection of vestibular and auditory functions should also be considered. Treatment options for Ménière disease include lifestyle modifications, medical treatment, and surgical intervention. Recent treatment algorithms aim to gradually escalate the invasiveness of the treatment to assist in developing a more uniform treatment approach. Nanomaterials, including nanoparticles and nanocarriers, offer an array of novel diagnostic and therapeutic applications for achieving effective drug delivery into the inner ear of patients with Ménière disease. New treatment drugs, such as SPI-1005 (Sound Pharmaceuticals) are currently under clinical trial. Furthermore, drugs are also being repurposed and investigated for their potential in treating Ménière disease. Discussion and Conclusion: Developing new drugs and investigating the pathophysiology of Ménière disease for subtyping is emerging. These may direct the future diagnosis and treatment of the disease and facilitate a better understanding of disease mechanisms. Patients with different subtypes of Ménière disease may require different treatment strategies, which can be achieved by personalized therapy, accurate prognosis prediction, and even, disease prevention. [ABSTRACT FROM AUTHOR]

Substantial evolution in the treatment of metastatic renal cell carcinoma (RCC) has occurred in recent years with notable changes in the first-line setting. Doublet combination therapy with either two immune checkpoint inhibitors or a combination of an immune checkpoint and tyrosine kinase inhibitor is considered the standard of care. These regimens have led to a significant improvement in clinical outcomes and disease prognosis. [ABSTRACT FROM AUTHOR]

Psychoactive substances such as psilocybin and 3,4‐methylenedioxy‐methamphetamine (MDMA) are currently being investigated for a variety of psychiatric indications including major depressive disorder and post‐traumatic stress disorder. It is critical that clinicians working in the mental health field understand the regulatory framework that balances access and control for such substances. While both psilocybin and MDMA are designated as "Breakthrough Therapy" by the Food and Drug Administration (FDA), they remain classified as Schedule I substances under the Controlled Substances Act (CSA) of 1970. There are programs such as Expanded Access (EA) and federal Right‐to‐Try (RTT) legislation that can accommodate patient access to investigational drugs under certain circumstances, but these programs are not without their limits—particularly for Schedule I substances that do not currently have an accepted medical use per the CSA. It is in the clinical community's best interest to understand the administrative procedures, key court cases, and federal legislative initiatives related to these substances in order to make well‐informed decisions for themselves and their patients. Furthermore, understanding the administrative proceedings related to controlled substances will also allow subject matter experts to participate in and shape the policies governing such substances. [ABSTRACT FROM AUTHOR]

Dual-Pocket Inhibition of Nav Channels by the Antiepileptic Drug Lamotrigine Huang J, Fan X, Jin X, Teng L, Yan N. Proc Natl Acad Sci USA. 2023;120(41):e2309773120. doi:10.1073/pnas.2309773120 Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs. [ABSTRACT FROM AUTHOR]

This article discusses the case of a 45-year-old male who was envenomated by his pet Trimeresurus insularis, a blue Indonesian pit viper. The patient presented to an emergency department in the United States and consultation with a poison center and medical toxicologist was obtained. Although Thai green pit viper antivenom is not approved by the US FDA, it was recommended based on in vitro data. The patient was transferred to another hospital to acquire the antivenom and received multiple doses, resulting in improvement in pain and swelling. Challenges in managing exotic snake envenomation in the US were highlighted, including the need for reimbursement to lending institutions and the regulatory requirements for using foreign antivenoms. Preemptive relationship development between poison centers, hospital pharmacies, IRBs, and venom lending facilities was suggested to navigate these challenges. [Extracted from the article]

Background: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. Methods: Research-grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rat, a rodent model of retinal degeneration such as retinitis pigmentosa. An investigational new drug (IND)-enabling study with CNS10-NPC was performed in the same rodent model. Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in a large animal model with Yucatan minipigs. Results: Both research-grade hNPC and clinical-grade hNPC can survive and provide functional and morphological protection in a dose-dependent fashion in RCS rats and the optimal cell dose was defined and used in IND-enabling studies. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a good laboratory practice (GLP) toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model with the Yucatan minipig, which has an eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. Conclusions: These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa. [ABSTRACT FROM AUTHOR]

Simple Summary: This research study focuses on the P-cadherin protein, which is found in many types of tumors, and could be a potential target for therapy. FF-21101, a human–mouse chimeric monoclonal antibody that targets P-cadherin, was labeled with indium-111(111In) and investigated for biodistribution and radiation doses in six cynomolgus macaques. To assess the radiation profile distribution and clearance of FF-21101(111In), we performed whole-body imaging and generated time–activity curves. The lungs, spleen, liver, kidneys, and heart wall received the highest radiation dose estimates for FF-21101(111In). These findings led us to estimate the radiation doses that would be delivered to different organs if this antibody was labeled with yttrium-90 (90Y) and used in targeted radioimmunotherapy in patients. FF-21101 shows potential for clinical application in humans, according to biodistribution data obtained from macaques. Based on these results, an investigational new drug application was filed with the FDA for a Phase I clinical trial. P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human–mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were defined on aligned reference CT and serial SPECT images. Organs with the highest estimated dose values (mSv/MBq) for FF-21101(111In) were the lungs (0.840), spleen (0.816), liver (0.751), kidneys (0.629), and heart wall (0.451); and for FF-21101(90Y) dose values were: lungs (10.49), spleen (8.21), kidneys (5.92), liver (5.46), and heart wall (2.61). FF-21101(111In) exhibits favorable biodistribution in cynomolgus macaques and estimated human dosimetric characteristics. Data obtained in this study were used to support the filing of an investigational new drug application with the FDA for a Phase I clinical trial. [ABSTRACT FROM AUTHOR]

Introduction: Symptoms reported following the administration of investigational drugs play an important role in decisions for registration and treatment guidelines. However, symptoms are subjective, and interview methods to quantify them are difficult to standardise. We explored differences in symptom reporting across study sites of a multicentre antimalarial trial, with the aim of informing trial design and the interpretation of safety and tolerability data. Methods: Data were derived from the IMPROV trial, a randomised, placebo-controlled double blinded trial of high dose primaquine to prevent Plasmodium vivax recurrence conducted in eight study sites in Afghanistan, Ethiopia, Indonesia and Vietnam. At each follow up visit a 13-point symptom questionnaire was completed. The number and percentage of patients with clinically relevant symptoms following the administration of primaquine or placebo, were reported by study site including vomiting, diarrhoea, anorexia, nausea, abdominal pain and dizziness. Multivariable logistic regression was used to estimate the confounder-adjusted site-specific proportion of each symptom. Results: A total of 2,336 patients were included. The greatest variation between sites in the proportion of patients reporting symptoms was for anorexia between day 0 and day 13: 97.3% (361/371) of patients in Arba Minch, Ethiopia, reported the symptom compared with 4.7% (5/106) of patients in Krong Pa, Vietnam. Differences attenuated slightly after adjusting for treatment arm, age, sex, day 0 parasite density and fever; with the adjusted proportion for anorexia ranging from 4.8% to 97.0%. Differences between sites were greater for symptoms graded as mild or moderate compared to those rated as severe. Differences in symptom reporting were greater between study sites than between treatment arms within the same study site. Conclusion: Despite standardised training, there was large variation in symptom reporting across trial sites. The reporting of severe symptoms was less skewed compared to mild and moderate symptoms, which are likely to be more subjective. Trialists should clearly distinguish between safety and tolerability outcomes. Differences between trial arms were much less variable across sites, suggesting that the relative difference in reported symptoms between intervention and control group is more relevant than absolute numbers and should be reported when possible. Trial registration: Clinicaltrials.gov: NCT01814683; March 20th, 2013. [ABSTRACT FROM AUTHOR]

Objective: Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small‐molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD. Methods: We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition. Results: Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up‐regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis. Conclusion: We highlight key biologic effects of apremilast on neutrophils in BD. [ABSTRACT FROM AUTHOR]

This study assesses Latin America and Caribbean countries' capacity to innovate new pharmaceuticals, defined as developing new drugs and vaccines, repurposing existing drugs, and inventing around patents to produce new drug variations. Vaccine innovation includes reengineering existing vaccines, developing new manufacturing methods, and the clinical development of unapproved vaccine candidates initiated elsewhere. [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias remain a common cause of death and disability. Antiarrhythmic drugs (AADs) and antiarrhythmic agents remain a cornerstone of current cardiac arrhythmia management, despite moderate efficacy and the potential for significant adverse proarrhythmic effects. Due to conceptual, regulatory and financial considerations, the number of novel antiarrhythmic targets and agents in the development pipeline has decreased substantially during the last few decades. However, several promising candidates remain and there are exciting developments in repurposing and reformulating already existing drugs for indications related to cardiac arrhythmias. This review discusses the key conceptual considerations for the development of new antiarrhythmic agents, summarizes new compounds and formulations currently in clinical development for rhythm control of atrial fibrillation, and highlights the potential for drug repurposing. Finally, future directions in AAD development are discussed. Together with an ever-increasing understanding of the molecular mechanisms underlying cardiac arrhythmias, these components support a cautiously optimistic outlook towards improved pharmacological treatment opportunities for patients suffering from cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

The article focuses on the outcomes of the A4 trial, which investigated the use of solanezumab, an anti-amyloid antibody, in cognitively unimpaired individuals with positive amyloid Positron Emission Tomography scans. Topics include the challenges of treating preclinical Alzheimer's disease, the dosage modifications during the trial, and the differences in targeting amyloid-beta species among various treatments.

The use of protease inhibitors in human immunodeficiency virus type 1 (HIV-1) treatment is limited by adverse effects, including metabolic complications. To address these challenges, efforts are underway in the pursuit of more potent and less toxic HIV-1 protease inhibitors. Repurposing existing drugs offers a promising avenue to expedite the drug discovery process, saving both time and costs compared to conventional de novo drug development. This study screened FDA-approved and investigational drugs in the DrugBank database for their potential as HIV-1 protease inhibitors. Molecular docking studies and cell-based assays, including anti-HIV-1 in vitro assays and XTT cell viability tests, were conducted to evaluate their efficacy. The study findings revealed that CBR003PS, an antibiotic currently in clinical use, and CBR013PS, an investigational drug for treating endometriosis and uterine fibroids, exhibited significant binding affinity to the HIV-1 protease with high stability. Their EC50 values, measured at 100% cell viability, were 9.4 nM and 36.6 nM, respectively. Furthermore, cell-based assays demonstrated that these two compounds showed promising results, with therapeutic indexes higher than 32. In summary, based on their favorable therapeutic indexes, CBR003PS and CBR013PS show potential for repurposing as HIV-1 protease inhibitors. [ABSTRACT FROM AUTHOR]

With the advent of newer drugs and formulations, the armamentarium to combat dermatophytosis is ever-expanding. However, we must be rational and scientific when choosing the drugs. This review is an attempt to summarise the recently approved and upcoming therapeutic options for dermatophytosis. [ABSTRACT FROM AUTHOR]

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study. [ABSTRACT FROM AUTHOR]

With the development of medical technology, tumor vaccines as a novel precise immunotherapy approach have gradually received attention in clinical applications. Against the backdrop of the global corona virus disease 2019 (COVID-19) outbreak, vaccine technology has further advanced. Depending on the types of antigens, tumor vaccines can be divided into whole-cell vaccines, peptide vaccines, messenger ribonucleic acid (mRNA) vaccines, recombinant virus vaccines, etc. Although some tumor vaccines have been marketed and achieved certain therapeutic effects, the results of tumor vaccines in clinical trials have been unsatisfactory in the past period. With the maturation of next-generation sequencing (NGS) technology and the continuous development of bioinformatics, dynamic monitoring of the entire process of tumor subpopulation development has become a reality, which has laid a solid foundation for personalized, neoantigen-centered therapeutic tumor vaccines. This article reviews the recent developments of tumor vaccines of different types, starts with lung cancer and summarizes the achievements of tumor vaccines in clinical applications, and provides an outlook for the future development of antigen-centered tumor vaccines. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) affects about 1% of the world's population and can lead to loss of joint function, reduced mobility, and permanent damage to cartilage and bone. Treatment options for RA primarily include disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, but the development of new drugs has complicated treatment decisions. Weighing treatment options for patients with RA largely depends on three major factors: efficacy, adverse reaction profile, and cost. A review of the literature supports methotrexate monotherapy as the current bestpractice model for treating RA, compared with combination therapy of methotrexate and/or other DMARDs. [ABSTRACT FROM AUTHOR]

Simple Summary: Hematological neoplasms afflict millions of children and adults yearly and are often uncurable due to refractory illness and recurrence. Therefore, new treatment approaches are required. The proto-oncogene c-MYC has been linked to carcinogenesis, particularly in hematological malignancies. Consequently, to develop new and effective therapies for blood cancers, it is essential to target c-MYC, specifically that c-MYC inhibitors have not yet received clinical approval. In this research, the verification of adapalene as a c-MYC inhibitor may be a glimmer of hope, especially that it is an already Food and Drug Administration (FDA)-approved drug, and its toxicity profiles, pharmacokinetics, and pharmacodynamics are well established. Our study presents a rationale that the discovery of adapalene as a c-MYC inhibitor may significantly lower the drug development costs of new anticancer medications. It also provides further insights in the future of adapalene-based designs that could result in more effective and targeted innovative therapies for multiple myeloma. The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of −7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (Kd value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC50 = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC50, 1 × IC50, 2 × IC50) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G2/M phase and increased the portion of cells in the sub-G0/G1 phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM. [ABSTRACT FROM AUTHOR]

The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical development are addressed in this review. A systematic literature search was conducted in three electronic databases (Medline, Web of Science, Scopus) and in the ClinicalTrials.gov register from 1 January 2016 to 1 June 2023 to identify Phase II, III and IV clinical trials evaluating drugs for the treatment of PHN. A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). In brief, there are several drugs in advanced clinical development for treating PHN with some of them reporting promising results. AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN. [ABSTRACT FROM AUTHOR]

There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress. The data suggest a disproportionate focus on the more well characterized kinases while much of the kinome remains comparatively understudied. It is noteworthy that tool compounds for understudied kinases have already been developed, and there is still untapped potential for further development in this chemical space. Finally, this review discusses many of the different strategies employed to generate selectivity between kinases. Given the large volume of information available and the progress made over the past 20 years when it comes to drugging kinases, we believe it is possible to develop a tool compound for every human kinase. We hope this review will prove to be both a useful resource as well as inspire the discovery of a tool for every kinase. [ABSTRACT FROM AUTHOR]

KEAP1 promotes the ubiquitin-dependent degradation of NRF2 by assembling into a CUL3-dependent ubiquitin ligase complex. Oxidative and electrophilic stress inhibit KEAP1 allowing NRF2 to accumulate for the transactivation of stress response genes. To date there are no structures of the KEAP1-CUL3 interaction nor binding data to show the contributions of different domains to their binding affinity. We determined a crystal structure of the BTB and 3-box domains of human KEAP1 in complex with the CUL3 N-terminal domain that showed a heterotetrameric assembly with 2:2 stoichiometry. To support the structural data, we developed a versatile TR-FRET-based assay system to profile the binding of BTB-domain-containing proteins to CUL3 and determine the contribution of distinct protein features, revealing the importance of the CUL3 N-terminal extension for high affinity binding. We further provide direct evidence that the investigational drug CDDO does not disrupt the KEAP1-CUL3 interaction, even at high concentrations, but reduces the affinity of KEAP1-CUL3 binding. The TR-FRET-based assay system offers a generalizable platform for profiling this protein class and may form a suitable screening platform for ligands that disrupt these interactions by targeting the BTB or 3-box domains to block E3 ligase function. [Display omitted] • A new crystal structure defines KEAP1 BTB and 3-box domain interactions with CUL3. • KEAP1 and CUL3 form a heteromeric 2:2 complex with a K D value of 0.2 μM. • A generalizable TR-FRET platform enables multimodal profiling of BTB proteins. • The investigational drug CDDO is a partial antagonist of the KEAP1-CUL3 interaction. [ABSTRACT FROM AUTHOR]

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signalling in the central nervous system is a non-hormonal strategy to modulate the activity of neurones that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause. This article summarizes the milestones in the development of fezolinetant leading to this first approval in this indication. [ABSTRACT FROM AUTHOR]