Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

在饱受药物研发屡屡失败、直接靶向KRAS的研究兴趣日渐式微且被认为难以攻克的时代落幕之际，新兴技术与策略正推动这一靶点的研究重获生机。正如既往报道，四氢吡啶并嘧啶类（tetrahydropyridopyrimidines）化合物被鉴定为KRASG12C的不可逆共价抑制剂，可结合于KRAS的开关II口袋（switch-II pocket），并与12位半胱氨酸形成共价键。研究人员结合基于结构的药物设计策略与聚焦式体外吸收、分布、代谢和排泄（in vitro absorption, distribution, metabolism and excretion, ADME）筛选方法，合成了该系列的衍生物，以提升其活性并降低代谢不良风险。本文详细报道了临床开发候选药物MRTX849的发现历程，该化合物是一款强效且高选择性的KRASG12C共价抑制剂。