8B6I

KRasG12C ligand complex

Summary for 8B6I

• Entry DOI: 10.2210/pdb8b6i/pdb
• Descriptor: GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: inhibitor complex, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 40539.04

Authors

Phillips, C.,Breed, J. (deposition date: 2022-09-27, release date: 2023-07-12, Last modification date: 2024-10-16)

Primary citation

Kettle, J.G.,Bagal, S.K.,Barratt, D.,Bodnarchuk, M.S.,Boyd, S.,Braybrooke, E.,Breed, J.,Cassar, D.J.,Cosulich, S.,Davies, M.,Davies, N.L.,Deng, C.,Eatherton, A.,Evans, L.,Feron, L.J.,Fillery, S.,Gleave, E.S.,Goldberg, F.W.,Cortes Gonzalez, M.A.,Guerot, C.,Haider, A.,Harlfinger, S.,Howells, R.,Jackson, A.,Johnstrom, P.,Kemmitt, P.D.,Koers, A.,Kondrashov, M.,Lamont, G.M.,Lamont, S.,Lewis, H.J.,Liu, L.,Mylrea, M.,Nash, S.,Niedbala, M.J.,Peter, A.,Phillips, C.,Pike, K.,Raubo, P.,Robb, G.R.,Ross, S.,Sanders, M.G.,Schou, M.,Simpson, I.,Steward, O.
Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRAS G12C with Demonstrable CNS Penetration.
J.Med.Chem., 66:9147-9160, 2023

PubMed Abstract: The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) 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 , AZD4747, a clinical development candidate for the treatment of KRAS-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRAS with an anticipated low clearance and high oral bioavailability profile in humans.

PubMed: 37395055
DOI: 10.1021/acs.jmedchem.3c00746

Experimental method

X-RAY DIFFRACTION (1.7 Å)