Drug Discovery Today最新文献

The plasma proteome offers a dynamic window into human physiology, enabling biomarker discovery, target prioritization, and drug repurposing for cardiovascular disease. Advances in high-throughput platforms, protein quantitative trait loci mapping, and machine learning reveal pleiotropic proteins and candidate causal targets, but translation requires rigorous safeguards. We propose a rigorous, tiered pipeline: discovery, mandatory orthogonal confirmation (targeted mass spectrometry or independent immunoassay), genetic prioritization with colocalization and sensitivity analyses, tissue-resolved functional validation, and prospective clinical evaluation with regulatory qualification. Integration with multi-omics, diverse cohorts, and electronic health record-embedded implementation studies, using HL7 Fast Healthcare Interoperability Resources and the Observational Medical Outcomes Partnership Common Data Model, can accelerate reproducible, equitable development of precision cardiovascular therapeutics.

This study examines the finances of 11 public companies that commercialize 21/25 drugs subject to price negotiation in 2024 or 2025 under the Inflation Reduction Act (IRA). From 2019-2023, these companies reported $2.5 trillion in revenue with $412.8 billion from sales of IRA drugs including $260.8 billion US sales, less than cumulative earnings or shareholder distributions. Estimated margins on sales were greater than reported average industry investments in development. Overall, reducing revenue from these drugs would not limit funds for operations or required returns on investment, though impacts on individual companies could vary and should be considered in price negotiations.

Biotech drug development is a high-risk, capital-intensive endeavor, requiring a balance between scientific advancement and financial reward. In this case study, we present BridgeBio's portfolio-based operating model, which integrates genetically validated targets with operational discipline and innovative financial structuring to enable rapid and scalable development. We situate BridgeBio's approach within the broader landscape of biotech operating archetypes and contrast it with more traditional approaches (e.g., single-asset, platform-based, venture-creation) models. This case study contributes to ongoing discussions about how portfolio-based strategies can improve the resilience and efficiency of biopharmaceutical innovation.

Bacterial resistance to antibiotics is increasing, seriously threatening human health; thus, the search for alternatives to antibiotics has become a significant research focus. Antimicrobial metals have long been used for their therapeutic properties, and different metals have specific antimicrobial mechanisms of action. Gallium shows broad antibacterial activity in vitro and in vivo, as well as synergistic antibacterial activity with other drugs, highlighting its potential clinical application for the treatment of infectious diseases. Here, we review research into the antimicrobial effects and mechanisms of action of gallium ions, as well as the clinical application of gallium ion-related drugs. Our review provides a theoretical reference for the application of the antimicrobial properties of gallium ions in clinical treatment.

Malaria remains a significant global health challenge, with rising drug resistance highlighting the urgent need for new therapeutic targets. Falcilysin (FLN), a conserved zinc metalloprotease essential for Plasmodium falciparum survival, has a pivotal role in hemoglobin degradation and processing transit peptides in the apicoplast. Recent studies reveal a druggable hydrophobic allosteric pocket and clarified the dynamic conformations of FLN, guiding rational inhibitor design. Multiple small-molecule classes have shown potent FLN inhibition across biochemical, cellular, and in vivo models. Key challenges include dual-organelle localization, selectivity over human homologs, and translating hits into clinical candidates. Future efforts should expand chemical diversity, explore covalent and proteolysis-targeting chimera (PROTAC) modalities, adopt multitarget strategies, and integrate cryo-electron microscopy (EM) and artificial intelligence (AI)-driven modeling for improved drug design.

Structural biology has proven to be a pivotal tool in early-stage drug discovery, particularly in the lead optimization phase. Structure-activity relationship approaches have enabled the successful modification of plant-derived natural products into approved therapeutic agents. Despite the well-documented antibacterial potential of many phytochemicals, the number of plant-derived antibacterial drugs reaching clinical development remains limited. We highlight key case studies involving crystal structures of bacterial targets complexed with plant-derived natural products, elucidating their binding modes and mechanisms of action. We discuss the current challenges and opportunities for medicinal chemists pursuing rational lead optimization in the development of antibacterial drugs.

Oncology is the biopharmaceutical industry's most active area for mergers and acquisitions (M&A) activity, reflecting both the scientific innovation and economics of precision medicines in the modern context. This review characterizes trends in 151 publicly disclosed pharmaceutical oncology M&A transactions between 2000 and 2019, showing that oncology dealmaking is increasingly concentrated among a small group of acquirers, that the bulk of acquisitions are of assets that are early in their development, and that deal structures increasingly emphasize milestone-linked and deferred payments. Together, these trends reveal how regulatory incentives, macroeconomic conditions, and productivity challenges have reshaped the scale and structure of oncology M&A in the precision-medicine era.

The emergence of chemotherapy resistance remains a pivotal challenge in oncology, driving the search for robust biomarkers of drug sensitivity. Schlafen 11 (SLFN11) is well established as a predictive biomarker for the response to DNA-damaging agents; however, its clinical translation is hindered by key challenges. This review systematically synthesizes current evidence on SLFN11, detailing its structure, multifaceted mechanisms, dynamic expression patterns, and epigenetic regulation. We evaluate detection methodologies, highlight the promise of dynamic monitoring via liquid biopsy, and explore rational combination therapies designed to leverage SLFN11 function. Finally, we provide a forward-looking perspective on integrating SLFN11 into biomarker-driven strategies and outline the clinical validation required to realize its full potential in precision oncology.

This study examines the relationship between startup growth and national drug discovery capability. Analysis of the countries of origin of compounds in US Phase 3 trials compared to those of FDA-approved drugs revealed growth in Asia, particularly in China. South Korea, Australia, and Canada also showed growth, whereas Japan, Germany, and the United Kingdom showed a declining number of drugs entering Phase 3 trials. National global drug discovery share growth and the proportion of post-2000 startups contributing to Phase 3 candidates were strongly correlated, underscoring the importance of a robust startup ecosystem. Post-2000 startups produced more compounds that use new modalities. The findings highlight important implications for innovation policy to strengthen national drug discovery capability, as well as for biopharmaceutical alliance and investment strategies.

Most proteins remain 'undruggable' by traditional approaches, which are unable to engage targets because of a lack of well-defined binding pockets, causing a bottleneck in drug discovery. Molecular glue degraders (MGDs) have emerged as a promising therapeutic strategy for targeting previously undruggable proteins. However, despite their potential, only a few MGDs have received FDA approval, highlighting gaps in off-target effects, drug resistance, and substrate availability. Here, we discuss recent MGD breakthroughs driven by the integration of structure-based computational approaches and AI platforms, which have accelerated MGD design with improved accuracy. Looking ahead, advances in quantum computing and AI-based generative models might open pathways to innovative treatments, targeting diseases once considered incurable.