Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) , INF 280, 69120 Heidelberg, Germany.
J Med Chem. 2017 Dec 28;60(24):10188-10204. doi: 10.1021/acs.jmedchem.7b01447. Epub 2017 Dec 15.
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.
组蛋白去乙酰化酶（HDACs）是表观遗传基因调控的重要调节剂，此外还控制非组蛋白蛋白底物的活性。虽然已经获得了许多针对 HDACs 1-3 和 6 的有效选择性抑制剂，但对于其他亚型，关于选择性抑制剂及其抑制的后果知之甚少。本报告描述了作为有效和选择性 HDAC8 抑制剂的取代苯甲羟肟酸的开发。使用现有晶体结构进行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，并优化了针对效力和选择性的命中，包括在体外和细胞培养中。基于结构的设计、合成和体外筛选与细胞测试相结合，产生了有效的和选择性的 HDAC8 抑制剂，在细胞测试中显示出抗神经母细胞瘤活性。
