6T5U

KRasG12C ligand complex

Summary for 6T5U

• Entry DOI: 10.2210/pdb6t5u/pdb
• Descriptor: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: gtpase, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 40047.88

Authors

Phillips, C. (deposition date: 2019-10-17, release date: 2020-02-19, Last modification date: 2024-05-01)

Primary citation

Kettle, J.G.,Bagal, S.K.,Bickerton, S.,Bodnarchuk, M.S.,Breed, J.,Carbajo, R.J.,Cassar, D.J.,Chakraborty, A.,Cosulich, S.,Cumming, I.,Davies, M.,Eatherton, A.,Evans, L.,Feron, L.,Fillery, S.,Gleave, E.S.,Goldberg, F.W.,Harlfinger, S.,Hanson, L.,Howard, M.,Howells, R.,Jackson, A.,Kemmitt, P.,Kingston, J.K.,Lamont, S.,Lewis, H.J.,Li, S.,Liu, L.,Ogg, D.,Phillips, C.,Polanski, R.,Robb, G.,Robinson, D.,Ross, S.,Smith, J.M.,Tonge, M.,Whiteley, R.,Yang, J.,Zhang, L.,Zhao, X.
Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.
J.Med.Chem., 63:4468-4483, 2020

PubMed Abstract: Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRAS inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

PubMed: 32023060
DOI: 10.1021/acs.jmedchem.9b01720

Experimental method

X-RAY DIFFRACTION (1.72 Å)