Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 6, Pages 1137-1144Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00574
Keywords
Mutated EGFR; covalent inhibitors; a-chlorofluoroacetamide; chemical proteomics; non-small-cell lung cancer
Categories
Funding
- JSPS KAKENHI [JP17H06349, JP17K15483, 19H02854, JP15H05955]
- AMED [JP18am0101091]
- JSPS
- World Premier International Research Center Initiative, Japan
- Grants-in-Aid for Scientific Research [19H02854] Funding Source: KAKEN
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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 alpha-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.
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