7U8H

Discovery of a KRAS G12V Inhibitor in vivo Tool Compound starting from an HSQC-NMR based Fragment Hit

Summary for 7U8H

• Entry DOI: 10.2210/pdb7u8h/pdb
• Descriptor: GTPase KRas, 1H-benzimidazol-2-ylmethanethiol, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: kras, p21, gtp-binding protein, oncogenes, binder, hydrolase, inhibitor of sos-mediated, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 80367.01

Authors

Phan, J.,Fesik, S.W. (deposition date: 2022-03-08, release date: 2022-11-09, Last modification date: 2023-10-25)

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

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: 36300829
DOI: 10.1021/acs.jmedchem.2c01120

Experimental method

X-RAY DIFFRACTION (1.702 Å)