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

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• 作者：Daisuke Yasuda^a ; Mao Nakajima^a ; Akihiro Yuasa^a ; Rika Obata^a ; Kyoko Takahashi^a ; Tomoyuki Ohe^a ; ^{ohe-tm@pha.keio.ac.jp} ; Yoshinobu Ichimura^b ; Masaaki Komatsu^b ; Masayuki Yamamoto^c ; Riyo Imamura^d ; Hirotatsu Kojima^d ; Takayoshi Okabe^d ; Tetsuo Nagano^d ; Tadahiko Mashino^a ; ^{mashino-td@pha.keio.ac.jp}
• 关键词：p62/Sqstm1 ; p62 ; phosphorylated-p62 ; p-p62 ; protein-protein interaction ; PPI ; nuclear factor erythroid 2 related factor-2 ; Nrf2 ; Kelch-like ECH-associated protein 1 ; Keap1 ; human hepatocellular carcinoma ; HCC ; cerium ammonium nitrite ; CAN ; fluorescent polarization ; FP
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：26
• 期：24
• 页码：5956-5959
• 全文大小：746 K
• 卷排序：26

文摘

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.