Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors.
Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors.
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DOI：
10.1021/acsmedchemlett.7b00126
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发表时间：
2017-08
影响因子：
4.2
通讯作者：
T. Y. Taha;Shaimaa M. Aboukhatwa;Rachel C Knopp;N. Ikegaki;Hazem Abdelkarim;Jayaprakash Neerasa;Yunlong Lu;Raghupathi Neelarapu;T. Hanigan;G. Thatcher;P. Petukhov
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文献类型：
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作者：
T. Y. Taha;Shaimaa M. Aboukhatwa;Rachel C Knopp;N. Ikegaki;Hazem Abdelkarim;Jayaprakash Neerasa;Yunlong Lu;Raghupathi Neelarapu;T. Hanigan;G. Thatcher;P. Petukhov
组蛋白脱乙酰酶 8 (HDAC8) 是多种治疗应用的有前景的药物靶点。在这里，我们描述了一系列基于 C1 取代的四氢异喹啉 (TIQ) 的 HDAC8 抑制剂的建模、设计、合成和生物学评估。配体结合时熵损失的最小化以及结合位点独特的 HDAC8“开放”构象的使用产生了提高 HDAC8 效力和选择性的成功策略。基于 TIQ 的 3g 和 3n 分别表现出最高的 82 和 55 nM HDAC8 效力，以及比 HDAC1 分别高出 330 和 135 倍的选择性。与其他 I 类同工型相比，选择性相当或更好，而 HDAC6（II 类 HDAC 同工型）的抑制在 10 μM 时低于 50%。在神经母细胞瘤细胞系中评估了3g和3n的细胞毒性，3n表现出与PCI-34051相似或更好的浓度依赖性细胞毒性。 3g 和 3n 的选择性在 SH-SY5Y 细胞中得到证实，因为两者都不会增加组蛋白 H3 和 α-微管蛋白的乙酰化。新型 TIQ 化学型的发现为开发用于治疗应用的 HDAC8 选择性抑制剂铺平了道路。
Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.