Nature Reviews Drug Discovery最新文献_第5页

Targeting RNA structure to treat prostate cancer 靶向RNA结构治疗前列腺癌

Nature Reviews Drug Discovery Pub Date : 2025-05-02 DOI: 10.1038/d41573-025-00077-z

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Application of new approach methodologies for nonclinical safety assessment of drug candidates 新方法方法在候选药物非临床安全性评估中的应用

Nature Reviews Drug Discovery Pub Date : 2025-05-02 DOI: 10.1038/s41573-025-01182-9

Mario Beilmann, Karissa Adkins, Harrie C. M. Boonen, Philip Hewitt, Wenyue Hu, Robert Mader, Susanne Moore, Payal Rana, Thomas Steger-Hartmann, Remi Villenave, Terry van Vleet

{"title":"Application of new approach methodologies for nonclinical safety assessment of drug candidates","authors":"Mario Beilmann, Karissa Adkins, Harrie C. M. Boonen, Philip Hewitt, Wenyue Hu, Robert Mader, Susanne Moore, Payal Rana, Thomas Steger-Hartmann, Remi Villenave, Terry van Vleet","doi":"10.1038/s41573-025-01182-9","DOIUrl":"https://doi.org/10.1038/s41573-025-01182-9","url":null,"abstract":"The development of new approach methodologies (NAMs) and advances with in vitro testing systems have prompted revisions in regulatory guidelines and inspired dedicated in vitro/ex vivo studies for nonclinical safety assessment. This Review by a safety reflection initiative subgroup of the European Federation of Pharmaceutical Industries and Associations (EFPIA)/Preclinical Development Expert Group (PDEG) summarizes the current state and potential application of in vitro studies using human-derived material for safety assessment in drug development. It focuses on case studies from recent projects in which animal models alone proved to be limited or inadequate for safety testing. It further highlights four categories of drug candidates for which alternative in vitro approaches are applicable and discusses progress in using in vitro testing solutions for safety assessment in these categories. Finally, the article highlights new risk assessment strategies, initiatives and consortia promoting the advancement of NAMs. This collective work is meant to encourage the use of NAMs for more human-relevant safety assessment, which should ultimately result in reduced animal testing for drug development.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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TIM-3 regulates microglial function TIM-3调节小胶质细胞功能

Nature Reviews Drug Discovery Pub Date : 2025-05-02 DOI: 10.1038/d41573-025-00078-y

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Understanding LAG3 immune checkpoint function 了解LAG3免疫检查点功能

Nature Reviews Drug Discovery Pub Date : 2025-05-02 DOI: 10.1038/d41573-025-00076-0

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Ramping up mitochondrial DNA replication 加快线粒体DNA的复制

Nature Reviews Drug Discovery Pub Date : 2025-05-02 DOI: 10.1038/d41573-025-00079-x

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GLP-1-based therapies for diabetes, obesity and beyond 以glp -1为基础的糖尿病、肥胖症及其他疾病的治疗

Nature Reviews Drug Discovery Pub Date : 2025-04-25 DOI: 10.1038/s41573-025-01183-8

Daniel J. Drucker

{"title":"GLP-1-based therapies for diabetes, obesity and beyond","authors":"Daniel J. Drucker","doi":"10.1038/s41573-025-01183-8","DOIUrl":"https://doi.org/10.1038/s41573-025-01183-8","url":null,"abstract":"Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics. ","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New antifungal tackles drug-resistant infections 新的抗真菌药物治疗耐药感染

Nature Reviews Drug Discovery Pub Date : 2025-04-24 DOI: 10.1038/d41573-025-00074-2

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The impact of accelerated drug marketing registration procedures on the review and approval of new drugs in China 加快药品上市注册程序对中国新药审批的影响

Nature Reviews Drug Discovery Pub Date : 2025-04-23 DOI: 10.1038/d41573-025-00070-6

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Shaping secondary pharmacology panels of the future: evolving target selection criteria for safety panels 塑造未来的二级药理学小组：发展安全小组的目标选择标准

Nature Reviews Drug Discovery Pub Date : 2025-04-22 DOI: 10.1038/s41573-025-01184-7

Friedemann Schmidt, Richard J. Brennan, Steve Jenkinson, Jean-Pierre Valentin

{"title":"Shaping secondary pharmacology panels of the future: evolving target selection criteria for safety panels","authors":"Friedemann Schmidt, Richard J. Brennan, Steve Jenkinson, Jean-Pierre Valentin","doi":"10.1038/s41573-025-01184-7","DOIUrl":"https://doi.org/10.1038/s41573-025-01184-7","url":null,"abstract":"We appreciate the thoughtful commentary by Maciag and Karamyan1 on our 2024 publication ‘The state of the art in secondary pharmacology and its impact on the safety of new medicines’2. In this paper, we reviewed secondary pharmacology data and profiling strategies from 18 pharmaceutical companies and recommended the implementation of an expanded core safety panel consisting of 77 diverse targets (Safety-77). The main aim of such screening panels is to identify potential human safety liabilities of novel molecules across all indications and chemotypes. To serve its purpose, the panel was balanced with respect to diversity of target families and mechanisms of toxicities, but it was also kept feasible with respect to its size.Maciag and Karamyan highlight the underrepresentation of non-kinase enzymes in our recommended assay panels and suggest the consideration of non-kinase enzymes such as neprilysin, cathepsins, carbonic anhydrases, thromboxane A synthase and xanthine oxidase due to risks of adverse events associated with activity against these enzymes. Studies by regulatory agencies have shown that inhibition of enzymes could be implicated in adverse events and that enzymes have comparable or higher hit rates than other targets (see Related links).","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enzymes in secondary pharmacology screening panels: is there room for improvement? 二级药理学筛选组中的酶：还有改进的空间吗？

Nature Reviews Drug Discovery Pub Date : 2025-04-22 DOI: 10.1038/s41573-025-01173-w

Monika Maciag, Vardan T. Karamyan

{"title":"Enzymes in secondary pharmacology screening panels: is there room for improvement?","authors":"Monika Maciag, Vardan T. Karamyan","doi":"10.1038/s41573-025-01173-w","DOIUrl":"https://doi.org/10.1038/s41573-025-01173-w","url":null,"abstract":"A recent article by Brennan and colleagues (Nat. Rev. Drug Discov. 23, 525–545; 2024)1 presents the findings of the largest collaborative effort among leading pharmaceutical companies on the application of secondary pharmacology screening to identify off-target activities of drug candidates, showing that wider adoption of standardized selectivity profiling has positively affected the safety of newer small-molecule drugs. The authors recommend an expanded panel of off-targets that is partly based on two earlier panels proposed by Bowes et al.2 and Lynch et al.3. We applaud Brennan and colleagues for completing this important collaborative work and expect their study will impact drug development substantially. Nevertheless, we want to use this opportunity to discuss an overlooked issue of non-kinase enzyme representation in the screening panels recommended thus far.The three noted panels include a partially overlapping set of targets associated with well-characterized safety concerns and are comprised of 44 (Bowes-44)2, 70 (Lynch-70)3, and 77 (Brennan-77)1 targets, covering the main pharmacological classes. Regarding enzymes, these panels only include 6 to 9 non-kinase enzymes, comprising 12% of all targets in the latest Brennan-77 panel (Fig. 1c). Since enzymes are a leading category for the ‘to-be’ and currently approved drugs, it is surprising that the share of enzymes in selectivity panels remains so limited. This underrepresentation is further highlighted by a recent study from Amgen showing the involvement of enzymes in about one-third of drug-related adverse events (23% non-kinase enzymes and 10% kinases)4. Similarly, an FDA study on the secondary pharmacology of investigational new drugs concluded that enzymes are tested less frequently than other targets despite comparable or higher hit rates5.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0