Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRAS.

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ID: 92793
2020
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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.
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kettle2020structurebasedjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Kettle, Jason Grant;Bagal, Sharan;Bickerton, Sue;Bodnarchuk, Michael Steven;Breed, Jason;Carbajo, Rodrigo J;Cassar, Doyle;Chakraborty, Atanu;Cosulich, Sabina;Cumming, Iain;Davies, Michael;Eatherton, Andrew;Evans, Laura;Feron, Lyman J;Fillery, Shaun M;Gleave, Emma Sarah;Goldberg, Frederick Woolf;Harlfinger, Stephanie;Hanson, Lyndsey;Howard, Martin;Howells, Rachel;Jackson, Anne;Kemmitt, Paul D;Kingston, Jennifer;Lamont, Scott;Lewis, Hilary;Li, Songlei;Liu, Libin;Ogg, Derek;Phillips, Christopher;Polanski, Radek;Robb, Graeme R;Robinson, David;Ross, Sarah;Smith, James;Tonge, Michael;Whiteley, Rebecca;Yang, Junsheng;Zhang, Longfei;Zhao, Xiliang;
Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b01720
URL
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