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

34 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2016.10.083

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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

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

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title = "Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity",

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.",

keywords = "Keap1, Nrf2, Protein-protein interaction inhibitor, p62/Sqstm1",

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

note = "Funding Information: This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), and Japan Agency for Medical Research and Development (AMED), 2012-2016. Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd",

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doi = "10.1016/j.bmcl.2016.10.083",

language = "English",

volume = "26",

pages = "5956--5959",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

AU - Yasuda, Daisuke

AU - Nakajima, Mao

AU - Yuasa, Akihiro

AU - Obata, Rika

AU - Takahashi, Kyoko

AU - Ohe, Tomoyuki

AU - Ichimura, Yoshinobu

AU - Komatsu, Masaaki

AU - Yamamoto, Masayuki

AU - Imamura, Riyo

AU - Kojima, Hirotatsu

AU - Okabe, Takayoshi

AU - Nagano, Tetsuo

AU - Mashino, Tadahiko

N1 - Funding Information: This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), and Japan Agency for Medical Research and Development (AMED), 2012-2016. Publisher Copyright: © 2016 Elsevier Ltd

PY - 2016

Y1 - 2016

N2 - 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.

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.

KW - Keap1

KW - Nrf2

KW - Protein-protein interaction inhibitor

KW - p62/Sqstm1

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JO - Bioorganic and Medicinal Chemistry Letters

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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