Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS<sup>G12C</sup>
Amin Li, Sujing Li, Peng George Wang, Chaojie Dang, Xin Fan, Mengran Chen, Dan Liu, Li Fu, Huan Liu, Wei Zhang, Yanping Wang, Yinxiang Wang
Abstract
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS G12C 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 G12C 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.