克拉斯
变构调节
GTP酶
癌症研究
化学
小分子
小型GTPase
鸟嘌呤核苷酸交换因子
癌症
突变体
计算生物学
信号转导
突变
生物
医学
受体
生物化学
内科学
基因
作者
Tonia Kirschner,Matthias Müller,Daniel Rauh
标识
DOI:10.1021/acs.jmedchem.3c02403
摘要
The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic RAS mutations disrupt this balance, favoring the active form and promoting proliferative signaling, thus rendering KRAS an appealing target for precision medicine in oncology. In 2013, Shokat and co-workers achieved a groundbreaking feat by covalently targeting a previously undiscovered allosteric pocket (switch II pocket (SWIIP)) of KRASG12C. This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Recent achievements in targeting various KRASG12X mutants, using SWIIP as a key binding pocket, are discussed. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.
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