{"title":"Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design Strategies.","authors":"Yang Zhou, Jibo Kang, Xiaoyun Lu","doi":"10.1021/acs.jmedchem.4c00361","DOIUrl":null,"url":null,"abstract":"<p><p>Solvent-front mutations have emerged as a common mechanism leading to acquired resistance to kinase inhibitors, representing a major challenge in the clinic. Several new-generation kinase inhibitors targeting solvent-front mutations have either been approved or advanced to clinical trials. However, there remains a need to discover effective, new-generation inhibitors. In this Perspective, we systematically summarize the general types of solvent-front mutations across the kinome and describe the development of inhibitors targeting some key solvent-front mutations. Additionally, we highlight the challenges and opportunities for the next generation of kinase inhibitors directed toward overcoming solvent-front mutations.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c00361","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Solvent-front mutations have emerged as a common mechanism leading to acquired resistance to kinase inhibitors, representing a major challenge in the clinic. Several new-generation kinase inhibitors targeting solvent-front mutations have either been approved or advanced to clinical trials. However, there remains a need to discover effective, new-generation inhibitors. In this Perspective, we systematically summarize the general types of solvent-front mutations across the kinome and describe the development of inhibitors targeting some key solvent-front mutations. Additionally, we highlight the challenges and opportunities for the next generation of kinase inhibitors directed toward overcoming solvent-front mutations.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.