Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries

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• 作者：Takayoshi Suzuki ; Yosuke Ota ; Masaki Ri ; Masashige Bando ; Aogu Gotoh ; Yukihiro Itoh ; Hiroki Tsumoto ; Prima R. Tatum ; Tamio Mizukami ; Hidehiko Nakagawa ; Shinsuke Iida ; Ryuzo Ueda ; Katsuhiko Shirahige ; Naoki Miyata
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9562-9575
• 全文大小：739K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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 (IC₅₀ = 0.070 渭M), which was more potent than PCI-34058 (6) (IC₅₀ = 0.31 渭M), 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 (GI₅₀ = 3鈥?0 渭M). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.