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
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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。
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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.

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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
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