| Literature DB >> 32023060 |
Jason G Kettle1, Sharan K Bagal1, Sue Bickerton1, Michael S Bodnarchuk1, Jason Breed2, Rodrigo J Carbajo1, Doyle J Cassar1, Atanu Chakraborty1, Sabina Cosulich1, Iain Cumming1, Michael Davies1, Andrew Eatherton1, Laura Evans1, Lyman Feron1, Shaun Fillery1, Emma S Gleave2, Frederick W Goldberg1, Stephanie Harlfinger1, Lyndsey Hanson3, Martin Howard1, Rachel Howells1, Anne Jackson2, Paul Kemmitt1, Jennifer K Kingston1, Scott Lamont1, Hilary J Lewis1, Songlei Li4, Libin Liu4, Derek Ogg2, Christopher Phillips2, Radek Polanski2, Graeme Robb1, David Robinson1, Sarah Ross1, James M Smith1, Michael Tonge2, Rebecca Whiteley1, Junsheng Yang4, Longfei Zhang4, Xiliang Zhao4.
Abstract
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C 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 KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.Entities:
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Year: 2020 PMID： 32023060 DOI： 10.1021/acs.jmedchem.9b01720
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446