Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

doi:10.1021/acs.jmedchem.2c00369

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Article

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

Journal of medicinal chemistry - 12 May 2022

Kettle Jason G, Bagal Sharan K, Bickerton Sue, Bodnarchuk Michael S, Boyd Scott, Breed Jason, Carbajo Rodrigo J, Cassar Doyle J, Chakraborty Atanu, Cosulich Sabina, Cumming Iain, Davies Michael, Davies Nichola L, Eatherton Andrew, Evans Laura, Feron Lyman, Fillery Shaun, Gleave Emma S, Goldberg Frederick W, Hanson Lyndsey, Harlfinger Stephanie, Howard Martin, Howells Rachel, Jackson Anne, Kemmitt Paul, Lamont Gillian, Lamont Scott, Lewis Hilary J, Liu Libin, Niedbala Michael J, Phillips Christopher, Polanski Radek, Raubo Piotr, Robb Graeme, Robinson David M, Ross Sarah, Sanders Matthew G, Tonge Michael, Whiteley Rebecca, Wilkinson Stephen, Yang Junsheng, Zhang Wenman

Abstract excerpt

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 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline...

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

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