Forma Therapeutics, Inc. , 500 Arsenal Street, Suite 100 , Watertown , Massachusetts 02472 , United States.
J Med Chem. 2019 Jul 25;62(14):6575-6596. doi: 10.1021/acs.jmedchem.9b00362. Epub 2019 Jul 8.
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of yielded a preclinical candidate . The detailed preclinical ADME and pharmacology studies of support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.
精氨酸残基（R132）处的突变在各种人类癌症中经常被发现。用小分子抑制突变型异柠檬酸脱氢酶 1（mIDH1）已在临床上被验证为急性髓性白血病和多种实体瘤有前途的治疗方法。在此，我们报告了一系列喹啉酮的发现和优化，以提供具有对野生型 IDH1 选择性的有效且可口服生物利用的 mIDH1 抑制剂。与 mIDH1-R132H 复合物的早期先导化合物的 X 射线结构表明，抑制剂出乎意料地结合在变构部位。为改善化合物的体外和体内吸收、分布、代谢和排泄（ADME）特性所做的努力得到了一个临床前候选化合物。对化合物的详细临床前 ADME 和药理学研究支持进一步开发基于喹啉酮的 mIDH1 抑制剂作为人类临床试验中的治疗剂。
