9KPM

Crystal structure of KRAS-G12C in complex with compound 16 (JAB-16)

This is a non-PDB format compatible entry.

Summary for 9KPM

• Entry DOI: 10.2210/pdb9kpm/pdb
• Descriptor: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, 7-[2-azanyl-3,5-bis(chloranyl)-6-fluoranyl-phenyl]-6-chloranyl-1-(4-methyl-2-propan-2-yl-pyridin-3-yl)-2-oxidanylidene-4-(4-prop-2-enoylpiperazin-1-yl)-1,8-naphthyridine-3-carbonitrile, ... (5 entities in total)
• Functional Keywords: kras4b, g12c, gtpase, inhibitor, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 22339.37

Authors

Li, S.,Dang, C.,Fan, X.,Zhang, W.,Wang, P.,Qian, D.,Wang, Y.,Li, A. (deposition date: 2024-11-23, release date: 2025-03-12)

Primary citation

Li, A.,Li, S.,Wang, P.,Dang, C.,Fan, X.,Chen, M.,Liu, D.,Li, F.,Liu, H.,Zhang, W.,Wang, Y.,Wang, Y.
Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS G12C.
J.Med.Chem., 68:2422-2436, 2025

PubMed Abstract: 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.

PubMed: 39875337
DOI: 10.1021/acs.jmedchem.4c02939

Experimental method

X-RAY DIFFRACTION (1.41 Å)