9PIZ
Structure of KRAS-G12C bound to 1-[(4aR,10P,13R)-10-[5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-11-chloro-9-fluoro-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinolin-3(4H)-yl]prop-2-en-1-one (compound 15)
This is a non-PDB format compatible entry.
Summary for 9PIZ
| Entry DOI | 10.2210/pdb9piz/pdb |
| Descriptor | Isoform 2B of GTPase KRas, ACETATE ION, anti-KRAS heavy chain, ... (11 entities in total) |
| Functional Keywords | oncoprotein, inhibitor, covalent |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 68367.67 |
| Authors | |
| Primary citation | Landry, M.L.,Malhotra, S.,Beresini, M.,Chan, C.,Chan, E.,de la Cruz, C.C.,Endres, N.F.,Evangelista, M.,Gustafson, A.,Hu, D.,Hunsaker, T.,Hsu, P.,Izrayelit, Y.,La, H.,Saenz-Lopez Larrocha, P.,Lian, Q.,Merchant, M.,Mao, J.,Mroue, R.,Oh, A.,Plise, E.,Shao, C.,Siu, M.,Tran, J.C.,Wang, Y.,Wang, W.,Wei, B.,Wong, S.,Yen, C.W.,Zhou, Y.,Purkey, H.E.,Heffron, T.P.,Salphati, L. Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C. J.Med.Chem., 2026 Cited by PubMed Abstract: Mutant KRAS is highly prevalent in human cancer and has been actively pursued as a target for drug discovery. Much progress has been made in drugging KRAS G12C, owing to the ability of inhibitors to covalently target its oncogenic cysteine mutation at codon 12. A number of KRAS G12C inhibitors have advanced to clinical development and are being investigated for the treatment of a variety of solid tumors. Notably, many patients with KRAS G12C-positive non-small cell lung cancer develop brain metastases. Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved. PubMed: 41769711DOI: 10.1021/acs.jmedchem.5c02279 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.94 Å) |
Structure validation
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