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

doi:10.1016/j.bmcl.2016.10.083

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

MED - Medical Sciences

Research output: Contribution to journal › Article › peer-review

26 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 language	English
Pages (from-to)	5956-5959
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2016.10.083
Publication status	Published - 2016

Keywords

Keap1
Nrf2
Protein-protein interaction inhibitor
p62/Sqstm1

ASJC Scopus subject areas

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

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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

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, 2016, p. 5956-5959.

Research output: Contribution to journal › Article › peer-review

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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AU - Imamura, Riyo

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AU - Okabe, Takayoshi

AU - Nagano, Tetsuo

AU - Mashino, Tadahiko

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AB - 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.

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