Li Amin, Li Sujing, Wang Peng, Dang Chaojie, Fan Xinrui, Chen Mengran, Liu Dan, Li Fu, Liu Huan, Zhang Wei, Wang Yanping, Wang Yinxiang
Medicinal Chemistry Department, Jacobio Pharmaceuticals Group Co., Ltd., Beijing 100176, P. R. China.
Biology Department, Jacobio Pharmaceuticals Group Co., Ltd., Beijing100176, P. R. China.
J Med Chem. 2025 Feb 13;68(3):2422-2436. doi: 10.1021/acs.jmedchem.4c02939. Epub 2025 Jan 28.
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutation is commonly found in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Inhibitors that covalently modify the mutated codon 12 cysteine have completed proof-of-concept studies in the clinic. Here, we describe structure-based design and cocrystal-aided drug optimization of a series of compounds with the 1,8-naphthyridine-3-carbonitrile scaffold. Biopharmaceutical optimization of the resulting leads to improve the solubility of the compounds and block the possible metabolic hotspots led to the identification of JAB-21822, a covalent KRAS inhibitor with high potency and excellent cross-species pharmacokinetic properties. JAB-21822 has finished the pivotal Phase II clinical trials in NSCLC, and a new drug application was submitted to the National Medical Products Administration in 2024.
KRAS是人类癌症中最常见的驱动癌基因，KRAS突变常见于非小细胞肺癌（NSCLC）、结直肠癌（CRC）和胰腺导管腺癌（PDAC）。共价修饰突变的第12位密码子半胱氨酸的抑制剂已在临床上完成概念验证研究。在此，我们描述了一系列具有1,8-萘啶-3-腈支架的化合物基于结构的设计和共晶体辅助的药物优化。对所得化合物进行生物制药优化以提高其溶解度并阻断可能的代谢热点，从而鉴定出JAB-21822，一种具有高效力和优异跨物种药代动力学特性的共价KRAS抑制剂。JAB-21822已完成NSCLC的关键II期临床试验，并于2024年向国家药品监督管理局提交了新药申请。
