Building consensus on the application of organoid-based drug sensitivity testing in cancer precision medicine and drug development.

Patient-derived organoids (PDOs) have emerged as a promising platform for clinical and translational studies. A strong correlation exists between clinical outcomes and the use of PDOs to predict the efficacy of chemotherapy and/or radiotherapy. To standardize interpretation and enhance scientific communication in the field of cancer precision medicine, we revisit the concept of PDO-based drug sensitivity testing (DST). We present an expert consensus-driven approach for medication selection aimed at predicting patient responses. To further standardize PDO-based DST, we propose guidelines for clarification and characterization. Additionally, we identify several major challenges in clinical prediction when utilizing PDOs.

Development of methyl 5-((cinnamoyloxy)methyl)picolinate, exploring its bio-target potential aiming at CVD mediated by multiple proteins through surface and physiochemical analysis.

The emphasis on sustainable sources of drug development seems imminent with phytochemicals emerging as promising candidates due to their minimal probability of adverse effects. This study focuses on utilizing simple cinnamic acid and nicotinic acid derivatives as starting materials, employing an efficient synthetic protocol to obtain methyl 5-((cinnamoyloxy)methyl)picolinate targeting CVD mediated by multiple enzymes such as MAPK, PCSK9, MPO, SIRT1 and TNF-α. Comprehensive characterization of synthesized molecule is achieved through 1H, 13C, FT-IR, and HRMS methods. Additionally, the crystal structure was established via SC-XRD. Comparative analysis with the DFT-optimized structure identifies key nucleophilic and electrophilic regions for determining interactions with bio-targets. Notably, Compound 5 adheres to all drug-likeness criteria, further validated through screening similar pharmacophoric drugs from databases. Targeting bio-relevant areas with a specific focus on CVD drug development. The molecular docking studies elucidate ligand-protein interactions for better binding connectivity. This investigation further underscores the importance of sustainable practices, simple chemical synthesis, and computational approaches, contributing to the pursuit of eco-friendly drug development with enhanced safety profiles (MTT assay).

Poly(ADP-Ribose) Polymerase Inhibitor Development: Promising Strategies to Move Beyond Approved Indications.

Biomarker-based patient selection and rational combinations show promise in expanding the use of PARP inhibitors.

Large language models reshaping molecular biology and drug development.

The utilization of large language models (LLMs) has become a significant advancement in the domains of medicine and clinical informatics, providing a revolutionary potential for scientific breakthroughs and customized therapies. LLM models are trained on large datasets and exhibit the capacity to comprehend and analyze intricate biological data, encompassing genomic sequences, protein structures, and clinical health records. With the utilization of their comprehension of the language of biology, they possess the ability to reveal concealed patterns and insights that may evade human researchers. LLMs have been shown to positively impact various aspects of molecular biology, including the following: genomic analysis, drug development, precision medicine, biomarker development, experimental design, collaborative research, and accessibility to specialized expertise. However, it is imperative to acknowledge and tackle the obstacles and ethical implications involved. The careful consideration of data bias and generalization, data privacy and security, explainability and interpretability, and ethical concerns around responsible application is vital. The successful resolution of these obstacles will enable us to fully utilize the capabilities of LLMs, leading to substantial progress in the fields of molecular biology and pharmaceutical research. This progression also has the ability to bolster influential impacts for both the individual and the broader community.

[Future prospects for the development of novel agents for acute myeloid leukemia].

For nearly 40 years, combination therapy with cytarabine and anthracycline has been the standard of care for acute myeloid leukemia (AML). The cytogenetics and molecular biology of AML are now understood, and the treatment of AML has undergone dramatic changes in Japan with the launch of drugs such as FLT3 inhibitors, Bcl2 inhibitors, and hypomethylating agents since 2018. However, AML remains very difficult to cure, with a high relapse rate. Here, we review novel agents that have not yet been approved in Japan (CPX-351, IDH inhibitors, menin inhibitors, and oral azacitidine) as potential treatments for AML, as well as therapeutic antibodies (BiTEs, DARTs, immune checkpoint inhibitors) currently under investigation in clinical trials or in development. These novel agents are being investigated not only as monotherapy but also as combination therapy with intensive chemotherapy or azacitidine/venetoclax. The new era of AML treatment is expected to support a variety of goals, including leukemic cell elimination, long-term remission, and improved quality of life.

Hope on the Horizon: Promising Therapies for Steatotic Liver Disease.

Steatotic liver disease (SLD) is a highly prevalent chronic liver disease with significant challenges for global health. The pathophysiology of SLD involves an interplay among genetic, endocrine, and metabolic factors. Successful management of SLD entails accurate diagnosis and disease monitoring through noninvasive methods such as advanced imaging techniques and biomarkers. Many emerging pharmacotherapies for SLD are now in the pipeline, which target different pathways like collagen turnover, fibrogenesis, inflammation, and metabolism. The recent approval of resmetirom for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) has been a milestone in addressing the unmet medical need for an efficacious SLD treatment. Finally, the potential of personalized medicine approaches and interdisciplinary cooperation in improving patient outcomes and reducing disease burden should be strongly pursued. SIGNIFICANCE STATEMENT: The healthcare burden due to steatotic liver disease (SLD) is enormous. This perspective sheds light on the recent advances in understanding the pathophysiology and diagnosis of SLD as well as promising drug development approaches.

Testing dilemmas in the clinic: Lessons learned from biomarker-based drug development.

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.

Biased signalling in analgesic research and development.

Ligand bias offers a novel means to improve the therapeutic profile of drugs. With regard to G protein-coupled receptors involved in analgesia, it could be advantageous to develop such drugs if the analgesic effect is mediated by a different cellular signalling pathway than the adverse effects associated with the drug. Whilst this has been explored over a number of years for the µ receptor, it remains unclear whether this approach offers significant benefit for the treatment of pain. Nevertheless, the development of biased ligands at other G protein-coupled receptors in the CNS does offer some promise for the development of novel analgesic drugs in the future. Here we summarise and discuss the recent evidence to support this.

Prevalence and Impact of Bypassing or Overriding Phase 2 Trials in Neurologic Drug Development.

BACKGROUND AND OBJECTIVES: Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial ("bypass") or despite a negative phase 2 efficacy result ("override"). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes. METHODS: We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override. RESULTS: Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65). DISCUSSION: Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.

Autophagy mediated targeting degradation, a promising strategy in drug development.

Targeted protein degradation (TPD) technologies have become promising therapeutic approaches through degrading disease-causing proteins via the protein degradation system. Autophagy is a fundamental biological process with a high relationship to protein degradation, which belongs to one of two main protein degradation pathways, the autophagy-lysosomal system. Recently, various autophagy-based TPD techniques ATTECs, AUTACs, and AUTOTACs, etc, have also been gradually developed, and they have achieved efficient degradation potency for the targeted protein, expanding the potential of degradation for large-size proteins or protein aggregates. Herein, we introduce the machinery of autophagy and its relation to protein degradation, and multiple methods for using autophagy to specifically degrade target proteins.

Development of novel bisphenol derivatives with a membrane-targeting mechanism as potent gram-positive antibacterial agents.

Antibiotic resistance is becoming increasingly severe. The development of small molecular antimicrobial peptides is regarded as a promising design strategy for antibiotics. Here, a series of bisphenol derivatives with amphiphilic structures were designed and synthesized as antibacterial agents by imitating the design strategy of antimicrobial peptides. After a series of structural optimizations, lead compound 43 was identified, which exhibited excellent antibacterial activity against Gram-positive bacterial strains (MICs = 0.78-1.56 µg/mL), poor hemolytic activity (HC50 > 200 µg/mL), and low cytotoxicity (CC50 > 100 µg/mL). Further biological evaluation results indicated that 43 exerted antibacterial effects by directly destroying bacterial cell membranes and displayed rapid bactericidal properties (within 0.5-1 h), leading to a very low probability of drug resistance. Moreover, in a murine model of corneal infection, 43 exhibited a strong in vivo antibacterial efficacy. These findings indicate that 43 is a promising candidate compound for the treatment of bacterial infections.

DprE1 and Ddn as promising therapeutic targets in the development of novel anti-tuberculosis nitroaromatic drugs.

Tuberculosis remains the second deadliest infectious disease in humans and a public health threat due to the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. Therefore, it is urgent to identify new anti-tuberculosis treatments and novel therapeutic targets to prevent the emergence of resistance. In recent years, the study of anti-tuberculosis properties of nitroaromatic compounds has led to the identification of two novel biological targets, the deazaflavin (F420)-dependent nitroreductase Ddn and the decaprenylphosphoryl-ß-d-ribose 2'-epimerase DprE1. This review aims to show why Ddn and DprE1 are promising therapeutic targets and highlight nitroaromatic compounds interest in developing new anti-tuberculosis treatments active against MDR-TB and XDR-TB. Despite renewed interest in the development of new anti-tuberculosis nitroaromatic compounds, pharmaceutical companies often exclude nitro-containing molecules from their drug discovery programs because of their toxic and mutagenic potential. This exclusion results in missed opportunities to identify new nitroaromatic compounds and promising therapeutic targets.

D3 Receptor-Targeted Cariprazine: Insights from Lab to Bedside.

Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.

Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma.

According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development.

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.

The drug drought in maternal health: an ongoing predicament.

We developed a comprehensive database of medicines that are used or are being investigated for pre-eclampsia or eclampsia, preterm birth or labour, postpartum haemorrhage, intrauterine growth restriction, and fetal distress and that were in active development between 2000 and 2021. A total of 444 candidates were identified: approximately half of candidates were in active development, two-thirds had been repurposed after initially being used for another condition, and just under half were in preclinical studies. Only 64 candidates were in active late-stage (phase 3) development as of Oct 25, 2021, and given the slow pace of biomedical development, it could take years before any of these products eventually make it to market. A lack of innovation for maternal health medicines persists, and the market continues to fail pregnant individuals. There is a need for collective action from all relevant stakeholders to accelerate investment in the development of new or improved medicines for pregnancy-related conditions.

Doses Evaluated in Clinical Pharmacology Studies Investigating the Effect of Intrinsic and Extrinsic Factors on PK and Safety: Case Examples from Approved Drug Development Programs.

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

Inflammation and Huntington's disease - a neglected therapeutic target?

INTRODUCTION: Huntington's Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. As such, modulation of the immune system could be a potential therapeutic target for HD. AREAS COVERED: To date, the number of trials targeting immune aspects of HD has been limited. However, targeting it, may have great advantages over other therapeutic areas, given that many drugs already exist that have actions in this system coupled to the fact that inflammation can be measured both peripherally and, to some extent, centrally using CSF and PET imaging. In this review, we look at evidence that the immune system and the newly emerging area of the microbiome are altered in HD patients, and then present and discuss clinical trials that have targeted different parts of the immune system. EXPERT OPINION: We then conclude by discussing how this field might develop going forward, focusing on the role of imaging and other biomarkers to monitor central immune activation and response to novel treatments in HD.