Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.

直接阻碍驱动致癌基因功能的药物提供了卓越的疗效和治疗窗口。最近批准的突变体选择性小分子半胱氨酸反应性 K-Ras G12C 突变体共价抑制剂 sotorasib 提供了一个恰当的例子。KRAS是人类癌症中突变最频繁的原癌基因，尽管成功靶向 G12C 等位基因，但尚未描述针对KRAS其他热点突变体的靶向治疗。在这里，我们报告了共价靶向 K-Ras 中的 G12S 体细胞突变并抑制其致癌信号传导的小分子的发现。我们表明这些分子在表达 K-Ras(G12S) 的细胞中具有活性，但保留了野生型蛋白质。我们的研究结果提供了一种靶向癌基因中第二个体细胞突变的途径KRAS通过克服获得的丝氨酸残基的弱亲核性。我们描述的化学可以作为选择性靶向其他未激活丝氨酸的基础。