10NV

Structure of kRas G12C Bound to Inhibitor 13ba

This is a non-PDB format compatible entry.

Summary for 10NV

• Entry DOI: 10.2210/pdb10nv/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-7-(1,6-dimethyl-1H-indazol-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline-6-carbonitrile, ... (5 entities in total)
• Functional Keywords: kras, small gtpase, oncoprotein, inhibitor complex
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 40909.63

Authors

Shaffer, P.L.,Milligan, C. (deposition date: 2026-01-29, release date: 2026-04-15, Last modification date: 2026-04-29)

Primary citation

Waldo, J.P.,Krawczuk, P.J.,Kelly, C.B.,Callas, C.G.,Cisar, J.S.,Eccles, W.,Guerrero, C.A.,Hack, M.D.,Jones, W.M.,Keohane, C.E.,Li, L.S.,Meegalla, S.,Padilla-Salinas, R.,Rosano, R.J.,Shimkin, K.W.,Simonnet, Y.R.F.,Sitkoff, D.,Sookezian, A.,Winters, M.P.,Bush, T.L.,Cheung, S.T.,Del Rosario, A.M.,Hansen, R.,Janes, M.R.,Janjua, H.,Kazmi, F.,Kirkpatrick, R.,La, D.,Lenhart, R.,Lorenzi, M.V.,Liu, Y.,Mesens, N.,Milligan, C.M.,Murrey, H.,Peters, U.,Ren, P.,Richter, M.,Rizzolio, M.,Rao, S.,Shaffer, P.,Stratton, C.F.,Szewczuk, L.M.,Wen, J.,Wong, V.,Yanovich, C.,Laquerre, S.,Edwards, J.P.,Leonard, K.A.
Optimization of Covalent 6-Cyanoquinazoline KRAS G12C Inhibitors for the Treatment of Solid Tumors.
J.Med.Chem., 69:9163-9195, 2026

PubMed Abstract: The KRASG12C mutation is a critical therapeutic target in the management of solid tumors, owing to its role in oncogenic signaling. Recent advances in covalent inhibitors that target mutant KRAS cysteine-12 have demonstrated the potential to halt aberrant signaling associated with this historically "undruggable" target. Here, we report the identification of 6-cyanoquinazoline covalent irreversible KRASG12C inhibitors. Lead optimization used structure-based design to identify novel switch-II pocket-binding motifs and in silico models to forecast in vitro metabolic stability and permeability. Human dose was improved by maximizing the rate of covalent modification (kobs/[I]) of KRASG12C-GDP, along with optimizing ADME parameters, to identify potent, orally bioavailable lead molecule which demonstrated significant antitumor efficacy in the NCI-H1373 human lung adenocarcinoma xenograft model. Studies evaluating KRASG12C-GDP covalent target engagement, pharmacokinetics, and tumor growth inhibition estimated the efficacious human dose of to be 192 mg administered once daily (QD), using allometric scaling.

PubMed: 41921095
DOI: 10.1021/acs.jmedchem.5c03610

Experimental method

X-RAY DIFFRACTION (1.52 Å)