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Discovery of AZD4625, a covalent allosteric inhibitor of the mutant GTPase KRASG12C

DOI: 10.1021/acs.jmedchem.2c00369 DOI Help

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

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 65 , PAGES 6940 - 6952

State: Published (Approved)
Published: May 2022
Diamond Proposal Number(s): 20015

Abstract: 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 tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Journal Keywords: Conformation; Rodent models; Monomers; Anatomy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 16/05/2022 12:50

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)