Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer
Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer
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DOI：
10.1021/acs.jmedchem.9b02052
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发表时间：
2020-07-09
影响因子：
7.3
通讯作者：
Marx, Matthew A.
中科院分区：
文献类型：
--
作者：
Fell, Jay B.;Fischer, John P.;Marx, Matthew A.
结束了一个被药物开发失败所破坏的时代，并被对KRAS直接靶向的兴趣减弱和假定的棘手性所打断，新技术和策略正在帮助靶点的复兴。如先前所报道的，四氢吡啶并嘧啶被鉴定为KRAS（G12 C）的不可逆共价抑制剂，其结合在KRAS的开关-II口袋中并与半胱氨酸12形成共价键。使用基于结构的药物设计结合集中在体外吸收，分布，代谢和排泄筛选方法，合成类似物，以增加效力和减少代谢负债的这一系列。描述了临床开发候选药物MRTX 849作为KRAS（G12 C）的强效选择性共价抑制剂的发现。
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 KRAS(G12C) 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 KRAS(G12C) is described.