Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1–3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.

中文翻译：

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具有抗神经母细胞瘤活性的选择性组蛋白脱乙酰基酶8（HDAC8）抑制剂的基于结构的设计和生物学特性

组蛋白脱乙酰基酶（HDACs）是表观遗传基因调控的重要调节剂，还可以控制非组蛋白的蛋白质底物的活性。对于HDAC 1–3和6，已经获得了许多有效的选择性抑制剂，而对于其他亚型，对选择性抑制剂及其抑制作用的了解却很少。本报告描述了取代的苯氧肟酸作为有效的和选择性的HDAC8抑制剂的发展。使用可用晶体结构的对接研究已用于该系列化合物的基于结构的优化。在这项研究中，我们研究了HDAC8在癌细胞增殖中的作用，并优化了体外和细胞培养中命中率和选择性的命中。基于结构的设计，综合，