Nature Reviews Drug Discovery最新文献_第9页

Clinical development success rates for durable cell and gene therapies 持久细胞和基因疗法的临床开发成功率

Nature Reviews Drug Discovery Pub Date : 2025-02-27 DOI: 10.1038/d41573-025-00036-8

引用次数: 0

MYC in cancer: from undruggable target to clinical trials 癌症中的MYC：从无药靶点到临床试验

Nature Reviews Drug Discovery Pub Date : 2025-02-19 DOI: 10.1038/s41573-025-01143-2

Jonathan R. Whitfield, Laura Soucek

{"title":"MYC in cancer: from undruggable target to clinical trials","authors":"Jonathan R. Whitfield, Laura Soucek","doi":"10.1038/s41573-025-01143-2","DOIUrl":"https://doi.org/10.1038/s41573-025-01143-2","url":null,"abstract":"MYC is among the most infamous oncogenes in cancer. A notable feature that distinguishes it from other common oncogenes is that its deregulation is not usually due to direct mutation, but instead to its relentless activation by other oncogenic lesions. These signalling pathways funnel through MYC to execute the transcriptional programmes that eventually lead to the uncontrolled proliferation of cancer cells. Indeed, deregulated MYC activity may be linked to most — if not all — human cancers. Despite this unquestionable role of MYC in tumour development and maintenance, no MYC inhibitor has yet been approved for clinical use. The main reason is that MYC has long fallen into the category of ‘undruggable’ or ‘difficult-to-drug’ targets, mainly because of its intrinsically disordered structure, which is not amenable to traditional drug development strategies. However, in recent years, attempts to develop MYC inhibitors have multiplied, and the first clinical trials have been testing their efficacy in patients. We are finally reaching the point at which its inhibition seems clinically viable. This Review provides an overview of the various strategies to inhibit MYC, focusing on the most recently described inhibitors and those that have reached clinical trials.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443717","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

A new European platform for advancing regulatory science research 一个促进监管科学研究的新欧洲平台

Nature Reviews Drug Discovery Pub Date : 2025-02-10 DOI: 10.1038/d41573-025-00024-y

Liese Barbier, Pierpaolo Moscariello, Hubert G Leufkens, Ralf Herold, Anna Maria Gerdina Pasmooij

引用次数: 0

Voltage-gated sodium channels in excitable cells as drug targets 可兴奋细胞中作为药物靶点的电压门控钠通道

Nature Reviews Drug Discovery Pub Date : 2025-02-03 DOI: 10.1038/s41573-024-01108-x

Matthew Alsaloum, Sulayman D. Dib-Hajj, Dana A. Page, Peter C. Ruben, Adrian R. Krainer, Stephen G. Waxman

{"title":"Voltage-gated sodium channels in excitable cells as drug targets","authors":"Matthew Alsaloum, Sulayman D. Dib-Hajj, Dana A. Page, Peter C. Ruben, Adrian R. Krainer, Stephen G. Waxman","doi":"10.1038/s41573-024-01108-x","DOIUrl":"https://doi.org/10.1038/s41573-024-01108-x","url":null,"abstract":"Excitable cells — including neurons, muscle cells and cardiac myocytes — are unique in expressing high densities of voltage-gated sodium (NaV) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of ‘the’ sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (NaV1.1–NaV1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these NaV subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083527","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

Novel strategies to manage CAR-T cell toxicity 管理CAR-T细胞毒性的新策略

Nature Reviews Drug Discovery Pub Date : 2025-02-03 DOI: 10.1038/s41573-024-01100-5

Arthur Mulvey, Lionel Trueb, George Coukos, Caroline Arber

{"title":"Novel strategies to manage CAR-T cell toxicity","authors":"Arthur Mulvey, Lionel Trueb, George Coukos, Caroline Arber","doi":"10.1038/s41573-024-01100-5","DOIUrl":"https://doi.org/10.1038/s41573-024-01100-5","url":null,"abstract":"The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on–off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077445","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

FGF-based drug discovery: advances and challenges 基于fgf的药物发现：进展与挑战

Nature Reviews Drug Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41573-024-01125-w

Gaozhi Chen, Lingfeng Chen, Xiaokun Li, Moosa Mohammadi

{"title":"FGF-based drug discovery: advances and challenges","authors":"Gaozhi Chen, Lingfeng Chen, Xiaokun Li, Moosa Mohammadi","doi":"10.1038/s41573-024-01125-w","DOIUrl":"https://doi.org/10.1038/s41573-024-01125-w","url":null,"abstract":"The fibroblast growth factor (FGF) family comprises 15 paracrine-acting and 3 endocrine-acting polypeptides, which govern a multitude of processes in human development, metabolism and tissue homeostasis. Therapeutic endocrine FGFs have recently advanced in clinical trials, with FGF19 and FGF21-based therapies on the cusp of approval for the treatment of primary sclerosing cholangitis and metabolic syndrome-associated steatohepatitis, respectively. By contrast, while paracrine FGFs were once thought to be promising drug candidates for wound healing, burns, tissue repair and ischaemic ailments based on their potent mitogenic and angiogenic properties, repeated failures in clinical trials have led to the widespread perception that the development of paracrine FGF-based drugs is not feasible. However, the observation that paracrine FGFs can exert FGF hormone-like metabolic activities has restored interest in these FGFs. The recent structural elucidation of the FGF cell surface signalling machinery and the formulation of a new threshold model for FGF signalling specificity have paved the way for therapeutically harnessing paracrine FGFs for the treatment of a range of metabolic diseases.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050130","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 benefits of translating biomedical research at drug discovery institutes 药物研发机构转化生物医学研究的益处

Nature Reviews Drug Discovery Pub Date : 2024-09-26 DOI: 10.1038/d41573-024-00142-z

David J. Huggins, Jonathan Baell, Paul E. Brennan, Alex Burgin, Duncan E. Scott

引用次数: 0