Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

Daisuke Yasuda, Akihiro Yuasa, Rika Obata, Mao Nakajima, Kyoko Takahashi, Tomoyuki Ohe, Yoshinobu Ichimura, Masaaki Komatsu, Masayuki Yamamoto, Riyo Imamura, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Tadahiko Mashino

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.

Original languageEnglish
Pages (from-to)5006-5009
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number22
DOIs
Publication statusPublished - 2017 Nov 15

Keywords

  • High-throughput screening
  • Keap1
  • Metabolic stability
  • Nrf2
  • Protein-protein interaction inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Yasuda, D., Yuasa, A., Obata, R., Nakajima, M., Takahashi, K., Ohe, T., Ichimura, Y., Komatsu, M., Yamamoto, M., Imamura, R., Kojima, H., Okabe, T., Nagano, T., & Mashino, T. (2017). Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor. Bioorganic and Medicinal Chemistry Letters, 27(22), 5006-5009. https://doi.org/10.1016/j.bmcl.2017.10.008