6P8W
Crystal structure of human KRAS G12C covalently bound to an acryloylazetidine acetamide inhibitor.
Summary for 6P8W
| Entry DOI | 10.2210/pdb6p8w/pdb |
| Descriptor | GTPase KRas, CALCIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | inhibitor, gtpase, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 44054.54 |
| Authors | Mohr, C. (deposition date: 2019-06-08, release date: 2019-08-28, Last modification date: 2024-11-06) |
| Primary citation | Shin, Y.,Jeong, J.W.,Wurz, R.P.,Achanta, P.,Arvedson, T.,Bartberger, M.D.,Campuzano, I.D.G.,Fucini, R.,Hansen, S.K.,Ingersoll, J.,Iwig, J.S.,Lipford, J.R.,Ma, V.,Kopecky, D.J.,McCarter, J.,San Miguel, T.,Mohr, C.,Sabet, S.,Saiki, A.Y.,Sawayama, A.,Sethofer, S.,Tegley, C.M.,Volak, L.P.,Yang, K.,Lanman, B.A.,Erlanson, D.A.,Cee, V.J. Discovery ofN-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C. Acs Med.Chem.Lett., 10:1302-1308, 2019 Cited by PubMed Abstract: KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. , which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRAS identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRAS with submicromolar inhibition of downstream signaling in a KRAS-specific manner. PubMed: 31531201DOI: 10.1021/acsmedchemlett.9b00258 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
Download full validation report
