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

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