Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors
Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors
复制标题
DOI：
10.1021/acs.jmedchem.9b01180
复制
发表时间：
2020-01-09
影响因子：
7.3
通讯作者：
Cee, Victor J.
中科院分区：
文献类型：
--
作者：
Lanman, Brian A.;Allen, Jennifer R.;Cee, Victor J.
KRAS（G12C）已成为治疗实体瘤的一个有希望的靶点。针对突变半胱氨酸-12残基的共价抑制剂已被证明可以破坏这个长期“不可药物”靶标的信号传导；然而，临床可行的抑制剂尚未被确定。在这里，我们报告了利用我们在KRAS（G12C）中发现的一个隐口袋（H95/Y96/Q99）来鉴定适合临床开发的抑制剂的努力。本文描述了基于结构的设计工作，从而确定了一种新的喹唑啉酮支架，并进行了优化工作，克服了由于轴向手性联芳键的旋转受限而引起的构型稳定性问题。AMG 510是一种高效、选择性和耐受性良好的KRAS（G12C）抑制剂，目前处于I期临床试验（NCT03600883）。
KRAS(G12C) has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS(G12C) to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well -tolerated KRAS(G12C) inhibitor currently in phase I clinical trials (NCT03600883).