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

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 EGFR when compared
to clinically approved osimertinib. Mass-based chemical proteomics
analyses further revealed that 18 displayed high covalent
modification selectivity for the mutated EGFR in living cells. These
findings highlight the utility of CFA as a warhead of targeted covalent
inhibitors and the potential application of the CFA-pyrimidines for
treatment of non-small-cell lung cancer.