1. Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C
- Author
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Rodrigo J. Carbajo, S. Harlfinger, Lyman Feron, Jason Grant Kettle, E.S. Gleave, Hilary J. Lewis, L. Liu, A. Jackson, Doyle Joseph Cassar, Sharanjeet Kaur Bagal, David Robinson, Radoslaw Polanski, L. Zhang, M.R. Howard, Sabina Cosulich, L. Evans, Jason Breed, Graeme R. Robb, A. Chakraborty, Rachel L. Howells, Rebecca Whiteley, Scott G. Lamont, Lyndsey Hanson, J.K. Kingston, Michael Davies, Iain A. Cumming, Sarah Ross, Sue Bickerton, Paul D. Kemmitt, Derek Ogg, Andrew John Eatherton, James M. Smith, S. Li, Bodnarchuk, Frederick W. Goldberg, Christopher R. Phillips, X. Zhao, Jun Yang, Michael Tonge, and Shaun M. Fillery
- Subjects
0303 health sciences ,Chemistry ,Allosteric regulation ,Mutant ,GTPase ,01 natural sciences ,Small molecule ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,In vivo ,Drug Discovery ,Biophysics ,Molecular Medicine ,Structure–activity relationship ,Linker ,030304 developmental biology ,Cysteine - 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.
- Published
- 2020