8AFB
CRYSTAL STRUCTURE OF KRAS-G12C IN COMPLEX WITH COMPOUND 23 (BI-0474)
Summary for 8AFB
| Entry DOI | 10.2210/pdb8afb/pdb |
| Related | 7U90 |
| Descriptor | GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | kras, gtpase, g12c, complex, inhibitor, oncoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20414.08 |
| Authors | Boettcher, J.,Kessler, D. (deposition date: 2022-07-16, release date: 2022-11-09, Last modification date: 2024-11-06) |
| Primary citation | Broker, J.,Waterson, A.G.,Smethurst, C.,Kessler, D.,Bottcher, J.,Mayer, M.,Gmaschitz, G.,Phan, J.,Little, A.,Abbott, J.R.,Sun, Q.,Gmachl, M.,Rudolph, D.,Arnhof, H.,Rumpel, K.,Savarese, F.,Gerstberger, T.,Mischerikow, N.,Treu, M.,Herdeis, L.,Wunberg, T.,Gollner, A.,Weinstabl, H.,Mantoulidis, A.,Kramer, O.,McConnell, D.B.,W Fesik, S. Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS G12C Inhibitor. J.Med.Chem., 65:14614-14629, 2022 Cited by PubMed Abstract: Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS inhibitors. To date, KRAS inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRAS inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRAS inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants. PubMed: 36300829DOI: 10.1021/acs.jmedchem.2c01120 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.12 Å) |
Structure validation
Download full validation report
