Pyridylalanine-Containing Hydroxamic Acids as Selective HDAC6 Inhibitors
Pyridylalanine-Containing Hydroxamic Acids as Selective HDAC6 Inhibitors
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DOI：
10.1002/cmdc.200800196
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发表时间：
2009-02-01
期刊：
影响因子：
3.4
通讯作者：
Jung, Manfred
中科院分区：
文献类型：
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作者：
Schaefer, Stefan;Saunders, Laura;Jung, Manfred
我们合成了异羟肟酸与吡啶丙氨酸的子结构，并确定它们作为选择性抑制剂的人重组HDAC6。对HDAC6的体外选择性高达HDAC1的25倍，并通过Western印迹法证实，以评估癌细胞中微管蛋白相对于组蛋白乙酰化。使用HDAC 6同源性模型的对接研究表明，抑制剂的疏水帽基团与在底物结合通道入口附近形成子口袋的芳族残基相互作用。HDAC6选择性化合物对癌细胞的细胞毒性低于泛HDAC抑制剂。我们用蛋白酶体抑制剂硼替佐米显示的协同抗增殖活性表明了具有较低全身毒性的联合抗癌治疗的潜力。
We synthesized hydroxamic acids with a pyridylalanine substructure and identified them as selective inhibitors of human recombinant HDAC6. The in vitro selectivity was up to 25-fold for HDAC6 over HDAC1 and was confirmed by Western blotting to assess tubulin versus histone acetylation in cancer cells. Docking studies with an HDAC6 homology model suggested that the hydrophobic cap group of the inhibitors interacts with aromatic residues that form a sub-pocket near the entrance of the substrate binding channel. The HDAC6-selective compounds have less cytotoxicity toward cancer cells than do pan-HDAC inhibitors. The synergistic antiproliferative activity we showed with the proteasome inhibitor bortezomib suggests the potential for combination anticancer therapy with less general toxicity.