KRAS, one of the most prevalent oncogenes and sought-after anticancer targets, has eluded chemists for decades until an irreversible covalent strategy targeting a specific mutation (G12C) paved the way for the first KRAS inhibitors to reach the clinic. MRTX849 is one such clinical candidate with promising initial results in patients harboring the mutation. The impressive optimization story of MRTX849 highlights challenges and solutions in the development of covalent drugs, including the use of an α-fluoroacrylamide electrophile.

中文翻译：

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当KRAS掉落时击中。

KRAS是最普遍的致癌基因之一，也是广受欢迎的抗癌靶标，数十年来一直困扰着化学家，直到针对特定突变（G12C）的不可逆共价策略为首批KRAS抑制剂进入临床铺平了道路。MRTX849就是这样的一种临床候选药物，在具有该突变的患者中有望获得初步结果。MRTX849令人印象深刻的优化故事突出了共价药物开发中的挑战和解决方案，包括使用α-氟代丙烯酰胺亲电试剂。