7O70

KRasG12C ligand complex

Summary for 7O70

• Entry DOI: 10.2210/pdb7o70/pdb
• Descriptor: GTPase KRas, 1-[(4R,7S)-12-chloro-14-fluoro-13-(2-fluoro-6-hydroxyphenyl)-4-methyl-10-oxa-2,5,16,18-tetrazatetracyclo[9.7.1.0^(2,7).0^(15,19)]nonadeca-1(18),11,13,15(19),16-pentaen-5-en-1-one-yl]prop-2, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: inhibitor, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 40694.53

Authors

Phillips, C. (deposition date: 2021-04-12, release date: 2022-04-20, Last modification date: 2024-10-23)

Primary citation

Kettle, J.G.,Bagal, S.K.,Bickerton, S.,Bodnarchuk, M.S.,Boyd, S.,Breed, J.,Carbajo, R.J.,Cassar, D.J.,Chakraborty, A.,Cosulich, S.,Cumming, I.,Davies, M.,Davies, N.L.,Eatherton, A.,Evans, L.,Feron, L.,Fillery, S.,Gleave, E.S.,Goldberg, F.W.,Hanson, L.,Harlfinger, S.,Howard, M.,Howells, R.,Jackson, A.,Kemmitt, P.,Lamont, G.,Lamont, S.,Lewis, H.J.,Liu, L.,Niedbala, M.J.,Phillips, C.,Polanski, R.,Raubo, P.,Robb, G.,Robinson, D.M.,Ross, S.,Sanders, M.G.,Tonge, M.,Whiteley, R.,Wilkinson, S.,Yang, J.,Zhang, W.
Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRAS G12C .
J.Med.Chem., 65:6940-6952, 2022

PubMed Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of , AZD4625, a clinical development candidate for the treatment of KRAS positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRAS with an anticipated low clearance and high oral bioavailability profile in humans.

PubMed: 35471939
DOI: 10.1021/acs.jmedchem.2c00369

Experimental method

X-RAY DIFFRACTION (1.18 Å)