10JT

CRYSTAL STRUCTURE OF KIRSTEN RAT SARCOMA G12C COMPLEXED WITH GMPPNP AND COVALENTLY BOUND TO 1-[(2R,3R)-3-{[(7P)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{ [(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d] pyrimidin-4-yl](methyl)amino}-2-methylpyrrolidin-1-yl]-3-(pyrazin-2-yl)propan-1-one

This is a non-PDB format compatible entry.

Summary for 10JT

• Entry DOI: 10.2210/pdb10jt/pdb
• Descriptor: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, 1-[(2R,3R)-3-{[(7P)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl](methyl)amino}-2-methylpyrrolidin-1-yl]-3-(pyrazin-2-yl)propan-1-one, ... (5 entities in total)
• Functional Keywords: kras, gtpase, inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41450.12

Authors

Sheriff, S. (deposition date: 2026-01-22, release date: 2026-03-04, Last modification date: 2026-03-18)

Primary citation

Condakes, M.L.,Civiello, R.L.,Lakkaraju, S.K.,Sloane, J.L.,Chourb, L.S.,Downes, D.P.,Drexler, D.M.,Dzhekieva, L.,El-Samin, M.,Levins, C.,Meyer, M.J.,Mosure, K.,Parker, M.F.,Qi, J.,Ruzanov, M.,Sheriff, S.,Stedman, J.,Szapiel, N.,Thompson, R.L.,Zhang, Z.,Zhuo, X.,Stewart, M.L.,Bronson, J.J.
Optimization of Covalent Warhead Trajectory for KRAS G12C Active-State Inhibition.
J.Med.Chem., 69:5925-5934, 2026

PubMed Abstract: We describe here the impact of the covalent warhead trajectory on biochemical active-state potency, covalent kinetics, cellular potency, and pharmacokinetic parameters for KRAS inhibitors. Using structure-based design augmented with computational models, trajectories were identified that successfully enhanced compound potency without requiring any additional optimization of the parent scaffold. In contrast to the trajectories of approved and clinical-stage KRAS inactive state-selective inhibitors, which largely consist of a collinear arrangement of the core, (di)amine linker, and covalent warhead, these trajectories were characterized by an angled disposition of the covalent warhead. A cocrystal structure implicated an increased distance from the bound nucleotide of KRAS as the basis for this increase in potency, suggesting a general design principle for targeting the active state of KRAS.

PubMed: 41769786
DOI: 10.1021/acs.jmedchem.5c03306

Experimental method

X-RAY DIFFRACTION (1.489 Å)