9PZF

Structure of KRAS G12C bound to Compound 4

This is a non-PDB format compatible entry.

Summary for 9PZF

• Entry DOI: 10.2210/pdb9pzf/pdb
• Descriptor: Isoform 2B of GTPase KRas, 1-(4-{(7M)-7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl}piperazin-1-yl)propan-1-one, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: gtpase, inhibitor, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 44622.52

Authors

Kiefer, J.R.,Wang, W.,Oh, A.,Yu, C. (deposition date: 2025-08-11, release date: 2026-03-11)

Primary citation

Endres, N.F.,Do, S.,Mroue, R.,Terrett, J.A.,Saabye, M.,Oh, A.,Hunsaker, T.,Chan, E.,Tran, J.C.,Nguyen, L.K.,Lian, Q.,Ma, T.P.,Garner, T.,Gerosa, L.,Beresini, M.,Boudreau, A.,Bronner, S.M.,Cyr, P.,Ishisoko, N.,Izrayelit, Y.,Jiang, F.,Kellar, T.,La, H.,Labadie, S.,Lardy, M.,Liu, L.,Liu, W.,Miller, S.,Rudolph, J.,Plise, E.,Sellers, B.D.,Shao, C.,Wang, W.,Wang, Y.,Wei, W.,Wong, S.,Yu, C.,Yu, K.,Yuen, P.W.,Zang, R.,Zhang, C.,Zhou, Y.,Zhu, X.,Quinn, J.G.,Ye, X.,Kiefer, J.R.,Mao, J.,Evangelista, M.,Merchant, M.,Landry, M.L.,Malhotra, S.,Purkey, H.E.
Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.
J.Med.Chem., 2026

PubMed Abstract: KRAS G12C is one of the most prevalent oncogenic mutations in nonsmall cell lung cancer. Herein we describe the discovery and optimization of divarasib (GDC-6036), an orally available, highly potent, and selective covalent KRAS G12C inhibitor. We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.

PubMed: 41766690
DOI: 10.1021/acs.jmedchem.5c02272

Experimental method

X-RAY DIFFRACTION (1.84 Å)