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Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRAS G12C

DOI: 10.1021/acs.jmedchem.9b01720 DOI Help

Authors: Jason G. Kettle (AstraZeneca) , Sharan K. Bagal (AstraZeneca) , Sue Bickerton (AstraZeneca) , Michael S. Bodnarchuk (AstraZeneca) , Jason Breed (AstraZeneca) , Rodrigo J. Carbajo (AstraZeneca) , Doyle J. Cassar (AstraZeneca) , Atanu Chakraborty (AstraZeneca) , Sabina Cosulich (AstraZeneca) , Iain Cumming (AstraZeneca) , Michael Davies (AstraZeneca) , Andrew Eatherton (AstraZeneca) , Laura Evans (AstraZeneca) , Lyman Feron (AstraZeneca) , Shaun Fillery (AstraZeneca) , Emma Gleave (AstraZeneca) , Frederick W. Goldberg (AstraZeneca) , Stephanie Harlfinger (AstraZeneca) , Lyndsey Hanson (AstraZeneca) , Martin Howard (AstraZeneca) , Rachel Howells (AstraZeneca) , Anne Jackson (AstraZeneca) , Paul Kemmitt (AstraZeneca) , Jennifer K. Kingston (AstraZeneca) , Scott Lamont (AstraZeneca) , Hilary J. Lewis (AstraZeneca) , Songlei Li (Pharmaron Beijing Co., Ltd) , Libin Liu (Pharmaron Beijing Co., Ltd) , Derek Ogg (AstraZeneca) , Christopher Phillips (AstraZeneca) , Radek Polanski (AstraZeneca) , Graeme Robb (AstraZeneca) , David Robinson (AstraZeneca) , Sarah Ross (AstraZeneca) , James M. Smith (AstraZeneca) , Michael Tonge (AstraZeneca) , Rebecca Whiteley (AstraZeneca) , Junsheng Yang (Pharmaron Beijing Co., Ltd) , Longfei Zhang (Pharmaron Beijing Co., Ltd) , Xiliang Zhao (Pharmaron Beijing Co., Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 20015

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.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 19/02/2020 09:51

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)