Open AccessSelective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines
Author(s) -
Mami Sato,
Hirokazu Fuchida,
Naoya Shindo,
Keiko Kuwata,
Ken Tokunaga,
Guo Xiao-lin,
Ryo Inamori,
Keitaro Hosokawa,
Kosuke Watari,
Tomohiro Shibata,
Naoya Matsumoto,
Satoru Koyanagi,
Shigehiro Ohdo,
Masahiro Ono,
Akio Ojida
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00574
Subject(s) - t790m , covalent bond , chemistry , osimertinib , epidermal growth factor receptor , egfr inhibitors , small molecule , pharmacology , biochemistry , combinatorial chemistry , receptor , cancer research , biology , gefitinib , organic chemistry , erlotinib
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.