Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRAS<sup>G12C</sup>
Jason G. Kettle, Sharan K. Bagal, Sue Bickerton, Michael S. Bodnarchuk, J. Breed, Rodrigo J. Carbajo, Doyle J. Cassar, Atanu Chakraborty, Sabina Cosulich, Iain Cumming, Michael A. Davies, Andrew J. Eatherton, Laura Evans, Lyman J. Feron, Shaun Fillery, Emma S. Gleave, Frederick W. Goldberg, Stephanie Harlfinger, Lyndsey Hanson, Martin Howard, Rachel Howells, Anne Jackson, Paul D. Kemmitt, Jennifer Kingston, Scott Lamont, Hilary Lewis, Songlei Li, Libin Liu, D. Ogg, Christopher Phillips, Radek Polanski, Graeme R. Robb, David M. Robinson, Sarah J. Ross, James M. Smith, Michael Tonge, Rebecca Whiteley, Junsheng Yang, Longfei Zhang, Xiliang Zhao
Abstract
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.