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Article

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

Journal of medicinal chemistry - 13 Jul 2023

Kettle Jason G, Bagal Sharan K, Barratt Derek, Bodnarchuk Michael S, Boyd Scott, Braybrooke Erin, Breed Jason, Cassar Doyle J, Cosulich Sabina, Davies Michael, Davies Nichola L, Deng Chao, Eatherton Andrew, Evans Laura, Feron Lyman J, Fillery Shaun, Gleave Emma S, Goldberg Frederick W, Cortés González Miguel A, Guerot Carine, Haider Afreen, Harlfinger Stephanie, Howells Rachel, Jackson Anne, Johnström Peter, Kemmitt Paul D, Koers Alex, Kondrashov Mikhail, Lamont Gillian M, Lamont Scott, Lewis Hilary J, Liu Libin, Mylrea Megan, Nash Samuel, Niedbala Michael J, Peter Alison, Phillips Christopher, Pike Kurt, Raubo Piotr, Robb Graeme R, Ross Sarah, Sanders Matthew G, Schou Magnus, Simpson Iain, Steward Oliver

Abstract excerpt

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 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases....

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

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