Nature Reviews Drug Discovery最新文献_第2页

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

引用次数: 0

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

引用次数: 0

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

The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation 芳烃受体：治疗性免疫调节的修复靶点

Nature Reviews Drug Discovery Pub Date : 2025-04-17 DOI: 10.1038/s41573-025-01172-x

Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, Francisco J. Quintana

{"title":"The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation","authors":"Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, Francisco J. Quintana","doi":"10.1038/s41573-025-01172-x","DOIUrl":"https://doi.org/10.1038/s41573-025-01172-x","url":null,"abstract":"The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841218","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

Back to the drawing board for anhedonia drugs 重新开始治疗快感缺乏症的药物

Nature Reviews Drug Discovery Pub Date : 2025-04-16 DOI: 10.1038/d41573-025-00073-3

引用次数: 0

Back to therapeutic modality basics 回到治疗模式的基础

Nature Reviews Drug Discovery Pub Date : 2025-04-16 DOI: 10.1038/d41573-025-00072-4

引用次数: 0

FDA new drug approvals in Q1 2025 2025年第一季度FDA新药批准

Nature Reviews Drug Discovery Pub Date : 2025-04-14 DOI: 10.1038/d41573-025-00071-5

引用次数: 0

Analysis of China-to-West pharmaceutical licensing deals in 2024 2024 年中国对西方制药许可交易分析

Nature Reviews Drug Discovery Pub Date : 2025-04-04 DOI: 10.1038/d41573-025-00068-0

引用次数: 0