直接使用 K-Ras 抑制剂治疗癌症:治疗癌症的直接 K-Ras 抑制剂:进展、新见解和治疗耐药性的方法》(Progress, New Insights, and Approaches to Treat Resistance.

IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Annual review of pharmacology and toxicology Pub Date : 2024-01-23 Epub Date: 2023-07-31 DOI:10.1146/annurev-pharmtox-022823-113946
Ruth Nussinov, Hyunbum Jang
{"title":"直接使用 K-Ras 抑制剂治疗癌症:治疗癌症的直接 K-Ras 抑制剂:进展、新见解和治疗耐药性的方法》(Progress, New Insights, and Approaches to Treat Resistance.","authors":"Ruth Nussinov, Hyunbum Jang","doi":"10.1146/annurev-pharmtox-022823-113946","DOIUrl":null,"url":null,"abstract":"<p><p>Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-Ras<sup>G12C</sup>. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-Ras<sup>G12C</sup> with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in <i>cis</i>, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"231-253"},"PeriodicalIF":11.2000,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance.\",\"authors\":\"Ruth Nussinov, Hyunbum Jang\",\"doi\":\"10.1146/annurev-pharmtox-022823-113946\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-Ras<sup>G12C</sup>. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-Ras<sup>G12C</sup> with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in <i>cis</i>, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.</p>\",\"PeriodicalId\":8057,\"journal\":{\"name\":\"Annual review of pharmacology and toxicology\",\"volume\":\" \",\"pages\":\"231-253\"},\"PeriodicalIF\":11.2000,\"publicationDate\":\"2024-01-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annual review of pharmacology and toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1146/annurev-pharmtox-022823-113946\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/7/31 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annual review of pharmacology and toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1146/annurev-pharmtox-022823-113946","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/7/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

在此,我们讨论 K-Ras 抑制方法和耐药性情况。针对 K-RasG12C 的共价药物是一个突破。随后的创新利用了相同基因的药物组合,以及将 K-RasG12C 与上游调节剂或下游激酶的辅助药物共同靶向。然而,原发性、适应性和获得性耐药性不可避免地会出现。预先存在的突变负荷可以解释,即使是无法观察到影响的极其罕见的突变也能促进耐药性、不敏感细胞克隆的生长和增殖。统计数据证实了大多数与耐药性相关的突变都是顺式突变的预期,这说明了同等位基因合作效应的可能性很高。除了靶向 Ras 抑制剂和药物组合外,针对 Ras 突变体的双功能分子和创新的三复合抑制剂也在开发之中。由于对已有突变和正在发生的突变的身份和潜在贡献尚不清楚,因此选择药物组合是一项艰巨的任务。我们的综述概述了各种考虑因素,并提供了药理学和耐药性方面的新见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance.

Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-RasG12C. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-RasG12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in cis, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
27.80
自引率
0.00%
发文量
53
期刊介绍: Since 1961, the Annual Review of Pharmacology and Toxicology has been a comprehensive resource covering significant developments in pharmacology and toxicology. The journal encompasses various aspects, including receptors, transporters, enzymes, chemical agents, drug development science, and systems like the immune, nervous, gastrointestinal, cardiovascular, endocrine, and pulmonary systems. Special topics are also featured in this annual review.
期刊最新文献
How Biologics Have Changed the Drug Discovery Landscape. Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases. Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics. Evolving Approaches for Pharmacological Therapy of Obesity. Genetically Enriched Clinical Trials for Precision Development of Noncancer Therapeutics: A Scoping Review.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1