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

Mami Sato, Hirokazu Fuchida, Naoya Shindo, Keiko Kuwata, Keisuke Tokunaga, Guo Xiao-Lin, Ryo Inamori, Keitaro Hosokawa, Kosuke Watari, Tomohiro Shibata, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo, Mayumi Ono, Akio Ojida

研究成果: Contribution to journalArticle査読

3 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)1137-1144
ページ数8
ジャーナルACS Medicinal Chemistry Letters
11
6
DOI
出版ステータス出版済み - 6 11 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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