Shin Youngsook, Jeong Joon Won, Wurz Ryan P, Achanta Pragathi, Arvedson Tara, Bartberger Michael D, Campuzano Iain D G, Fucini Ray, Hansen Stig K, Ingersoll John, Iwig Jeffrey S, Lipford J Russell, Ma Vu, Kopecky David J, McCarter John, San Miguel Tisha, Mohr Christopher, Sabet Sudi, Saiki Anne Y, Sawayama Andrew, Sethofer Steven, Tegley Christopher M, Volak Laurie P, Yang Kevin, Lanman Brian A, Erlanson Daniel A, Cee Victor J
Departments of Therapeutic Discovery, Oncology Research, Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States.
ACS Med Chem Lett. 2019 Aug 20;10(9):1302-1308. doi: 10.1021/acsmedchemlett.9b00258. eCollection 2019 Sep 12.
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. , which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRAS identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRAS with submicromolar inhibition of downstream signaling in a KRAS-specific manner.
KRAS调节许多细胞过程，包括增殖、存活和分化。长期以来，KRAS的点突变体一直被认为是癌症的分子驱动因素。KRAS突变发生在约14%的肺腺癌、3-5%的结直肠癌中，在其他实体瘤中的发生率较低，是共价抑制剂有吸引力的治疗靶点。在此，我们披露了通过一个名为“化学型进化”的定制文库合成和筛选平台以及基于结构的设计发现的一类新型、强效且选择性的KRAS共价抑制剂。鉴定出由H95/Y96/Q99侧链界定的隐藏表面凹槽是优化这类分子的关键。系列最佳范例与GDP-KRAS的半胱氨酸12发生快速共价反应，以KRAS特异性方式对下游信号传导产生亚微摩尔抑制作用。
