Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries
Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries
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DOI：
10.1021/jm300837y
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发表时间：
2012-11-22
影响因子：
7.3
通讯作者：
Miyata, Naoki
中科院分区：
文献类型：
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作者：
Suzuki, Takayoshi;Ota, Yosuke;Miyata, Naoki
为了找到HDAC 8选择性抑制剂，我们设计了一个HDAC抑制剂候选物库，每个候选物含有与活性位点锌离子配位的锌结合基团，通过三唑部分连接到与活性位点边缘上的残基相互作用的封端结构。通过使用点击化学合成这些化合物，筛选鉴定了HDAC 8选择性抑制剂，包括C149（IC 50 = 0.070 μ M），其比PCI-34058（6）（IC 50 = 0.31 μ M）（一种已知的HDAC 8抑制剂）更有效。分子建模表明，C149的苯硫基甲基与HDAC 8的独特疏水口袋结合，苯硫基甲基和异羟肟酸酯部分（由三唑部分固定）的取向对效力和选择性很重要。抑制剂引起细胞中粘附素的选择性乙酰化，并对T细胞淋巴瘤和神经母细胞瘤细胞产生生长抑制作用（GI（50）= 3-80 μ M）。这些发现表明HDAC 8选择性抑制剂具有作为抗癌剂的潜力。
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 mu M), which was more potent than PCI-34058 (6) (IC50 = 0.31 mu 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 (GI(50) = 3-80 mu M). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.