Selective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines.

ABSTRACT: Covalent modification of disease-associated proteins with small molecules is a powerful approach for achieving an increased and sustained pharmacological effect. To reduce the potential risk of nonselective covalent modification, molecular design of covalent inhibitors is critically important. We report herein the development of a targeted covalent inhibitor for mutated epidermal growth factor receptor (EGFR) (L858R/T790M) using α-chlorofluoroacetamide (CFA) as the reactive group. The chemically tuned weak reactivity of CFA was suitable for the design of third-generation EGFR inhibitors that possess the pyrimidine scaffold. The structure-activity relationship study revealed that CFA inhibitor 18 (NSP-037) possessed higher inhibition selectivity to the mutated EGFR over wild-type EGF

SUBMITTER: Sato M 

PROVIDER: S-EPMC7294701 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature