Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRAS<sup>G12C</sup>
Jason G. Kettle, Sharan K. Bagal, Sue Bickerton, Michael S. Bodnarchuk, Scott Boyd, J. Breed, Rodrigo J. Carbajo, Doyle J. Cassar, Atanu Chakraborty, Sabina Cosulich, Iain Cumming, Michael Davies, Nichola L. Davies, Andrew J. Eatherton, Laura Evans, Lyman J. Feron, Shaun Fillery, Emma S. Gleave, Frederick W. Goldberg, Lyndsey Hanson, Stephanie Harlfinger, Martin Howard, Rachel Howells, Anne Jackson, Paul D. Kemmitt, Gillian M. Lamont, Scott G. Lamont, Hilary Lewis, Libin Liu, Michael Niedbala, Christopher Phillips, Radek Polanski, Piotr Raubo, Graeme R. Robb, David M. Robinson, Sarah J. Ross, Matthew G. Sanders, Michael Tonge, Rebecca Whiteley, Stephen Wilkinson, Junsheng Yang, Wenman Zhang
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.