Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

Daisuke Yasuda, Mao Nakajima, Akihiro Yuasa, Rika Obata, 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

15 Citations (Scopus)

Abstract

The Keap1-Nrf2 system is involved not only in biological defense but also in malignancy progression and chemoresistance. The ubiquitin-binding protein p62/Sqstm1 (p62), which is highly expressed in several cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67. In this study, we established facile synthetic routes for K67 and derivatives with various side chains on the C-2 position of naphthalene ring. K67 possessed high selectivity in the inhibition of Keap1-p-p62. Other derivatives showed potent Keap1-Nrf2 and Keap1-p-p62 PPI inhibitory activities, though the selectivity between the two activities was lower than K67.

Original languageEnglish
Pages (from-to)5956-5959
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number24
DOIs
Publication statusPublished - 2016 Dec 15

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Derivatives
Proteins
Neoplasms
Ubiquitin
Gene expression
Cell Survival
Carrier Proteins
Chemical activation
Cells
Gene Expression
naphthalene
Sequestosome-1 Protein

Keywords

  • Keap1
  • Nrf2
  • p62/Sqstm1
  • Protein-protein interaction inhibitor

ASJC Scopus subject areas

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

Cite this

Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity. / Yasuda, Daisuke; Nakajima, Mao; Yuasa, Akihiro; Obata, Rika; Takahashi, Kyoko; Ohe, Tomoyuki; Ichimura, Yoshinobu; Komatsu, Masaaki; Yamamoto, Masayuki; Imamura, Riyo; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Mashino, Tadahiko.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 24, 15.12.2016, p. 5956-5959.

Research output: Contribution to journalArticle

Yasuda, D, Nakajima, M, Yuasa, A, Obata, R, Takahashi, K, Ohe, T, Ichimura, Y, Komatsu, M, Yamamoto, M, Imamura, R, Kojima, H, Okabe, T, Nagano, T & Mashino, T 2016, 'Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 24, pp. 5956-5959. https://doi.org/10.1016/j.bmcl.2016.10.083
Yasuda, Daisuke ; Nakajima, Mao ; Yuasa, Akihiro ; Obata, Rika ; Takahashi, Kyoko ; Ohe, Tomoyuki ; Ichimura, Yoshinobu ; Komatsu, Masaaki ; Yamamoto, Masayuki ; Imamura, Riyo ; Kojima, Hirotatsu ; Okabe, Takayoshi ; Nagano, Tetsuo ; Mashino, Tadahiko. / Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 24. pp. 5956-5959.
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