1. Academic Validation
  2. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C

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

  • J Med Chem. 2022 May 12;65(9):6940-6952. doi: 10.1021/acs.jmedchem.2c00369.
Jason G Kettle 1 Sharan K Bagal 1 Sue Bickerton 1 Michael S Bodnarchuk 1 Scott Boyd 1 Jason Breed 2 Rodrigo J Carbajo 1 Doyle J Cassar 1 Atanu Chakraborty 1 Sabina Cosulich 1 Iain Cumming 1 Michael Davies 1 Nichola L Davies 1 Andrew Eatherton 1 Laura Evans 1 Lyman Feron 1 Shaun Fillery 1 Emma S Gleave 2 Frederick W Goldberg 1 Lyndsey Hanson 3 Stephanie Harlfinger 1 Martin Howard 1 Rachel Howells 1 Anne Jackson 2 Paul Kemmitt 1 Gillian Lamont 1 Scott Lamont 1 Hilary J Lewis 1 Libin Liu 4 Michael J Niedbala 5 Christopher Phillips 2 Radek Polanski 2 Piotr Raubo 1 Graeme Robb 1 David M Robinson 1 Sarah Ross 1 Matthew G Sanders 1 Michael Tonge 2 Rebecca Whiteley 1 Stephen Wilkinson 1 Junsheng Yang 4 Wenman Zhang 4
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 2 Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 3 Oncology R&D, AstraZeneca, Alderley Park SK10 4TG, U.K.
  • 4 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China.
  • 5 Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
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.

Figures
Products