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

研究成果: Article

22 引用 (Scopus)

抜粋

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.

元の言語English
ページ(範囲)5956-5959
ページ数4
ジャーナルBioorganic and Medicinal Chemistry Letters
26
発行部数24
DOI
出版物ステータスPublished - 2016 12 15

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ASJC Scopus subject areas

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

これを引用

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, 26(24), 5956-5959. https://doi.org/10.1016/j.bmcl.2016.10.083