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Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kettle JG,Bagal SK,Bickerton S,Bodnarchuk MS,Breed J,Carbajo RJ,Cassar DJ,Chakraborty A,Cosulich S,Cumming I,Davies M,Eatherton A,Evans L,Feron L,Fillery S,Gleave ES,Goldberg FW,Harlfinger S,Hanson L,Howard M,Howe

doi

10.1021/acs.jmedchem.9b01720

subject

Has Abstract

pub_date

2020-05-14 00:00:00

pages

4468-4483

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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