title: Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries.
abstract: To find HDAC8-selective inhibitors, we designed a library of HDAC inhibitor candidates, each containing a zinc-binding group that coordinates with the active-site zinc ion, linked via a triazole moiety to a capping structure that interacts with residues on the rim of the active site. These compounds were synthesized by using click chemistry. Screening identified HDAC8-selective inhibitors including C149 (IC(50) = 0.070 μM), which was more potent than PCI-34058 (6) (IC(50) = 0.31 μM), a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethyl group of C149 binds to a unique hydrophobic pocket of HDAC8, and the orientation of the phenylthiomethyl and hydroxamate moieties (fixed by the triazole moiety) is important for the potency and selectivity. The inhibitors caused selective acetylation of cohesin in cells and exerted growth-inhibitory effects on T-cell lymphoma and neuroblastoma cells (GI(50) = 3-80 μM). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 403-8334, Japan. suzukit@koto.kpu-m.ac.jp
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.forename: Masashige
authors.initials: M
authors.lastname: Bando
authors.forename: Aogu
authors.initials: A
authors.lastname: Gotoh
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsumoto
authors.forename: Prima R
authors.initials: PR
authors.lastname: Tatum
authors.forename: Tamio
authors.initials: T
authors.lastname: Mizukami
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D057930:Click Chemistry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D008958:Models, Molecular; D009447:Neuroblastoma / Q000188:drug therapy*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D054852:Small Molecule Libraries; C409470:HDAC8 protein, human; D006655:Histone Deacetylases