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.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yasuda
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
authors.forename: Mao
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yuasa
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Obata
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: ohe-tm@pha.keio.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.affiliation: Department of Biochemistry, School of Medicine, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata-shi, Niigata, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Biochemistry, School of Medicine, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata-shi, Niigata, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Medical Biochemistry, Tohoku University School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai-shi, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Riyo
authors.initials: R
authors.lastname: Imamura
authors.affiliation: Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.affiliation: Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: mashino-td@pha.keio.ac.jp.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020703:ras GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C000620860:2-acetonyl-1,4-bis((4-etoxybenzensulfonyl)amino)naphthalene; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009281:Naphthalenes; C118585:P62 protein, human; D016601:RNA-Binding Proteins; D013449:Sulfonamides; D020703:ras GTPase-Activating Proteins; C031721:naphthalene; D015057:1-Naphthylamine
keywords: Keap1; Nrf2; Protein-protein interaction inhibitor; p62/Sqstm1