Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

doi:10.1021/acs.jmedchem.9b01720

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Article

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

Journal of medicinal chemistry - 14 May 2020

Kettle Jason G, Bagal Sharan K, Bickerton Sue, Bodnarchuk Michael S, Breed Jason, Carbajo Rodrigo J, Cassar Doyle J, Chakraborty Atanu, Cosulich Sabina, Cumming Iain, Davies Michael, Eatherton Andrew, Evans Laura, Feron Lyman, Fillery Shaun, Gleave Emma S, Goldberg Frederick W, Harlfinger Stephanie, Hanson Lyndsey, Howard Martin, Howells Rachel, Jackson Anne, Kemmitt Paul, Kingston Jennifer K, Lamont Scott, Lewis Hilary J, Li Songlei, Liu Libin, Ogg Derek, Phillips Christopher, Polanski Radek, Robb Graeme, Robinson David, Ross Sarah, Smith James M, Tonge Michael, Whiteley Rebecca, Yang Junsheng, Zhang Longfei, Zhao Xiliang

Abstract excerpt

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...

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

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PubMed metadata and Literature Corpus relationships. Corpus snapshot updated 7 Sept 2026. Manifest publication-graph-cohort-2026-09-07.1.

Source receipt: pubmed, retrieved 7 Sept 2026.

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