Zhao Chunlong, Zang Jie, Ding Qin'ge, Inks Elizabeth S, Xu Wenfang, Chou C James, Zhang Yingjie
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong, 250012, PR China.
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States.
Eur J Med Chem. 2018 Apr 25;150:282-291. doi: 10.1016/j.ejmech.2018.03.002. Epub 2018 Mar 6.
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (∼30-fold) which was confirmed by western blot analysis. It is worth noting that 12a, 12b and 12c displayed highly selective anti-proliferative activity to T-cell leukemia cell lines Jurkat, Molt-4 and neuroblastoma cell line SK-N-BE-(2). Such selective cytotoxicity was also observed in the well-known HDAC8 selective inhibitor PCI-34051 but not in the pan-HDAC inhibitors SAHA and PXD101, indicating that HDAC8 selective inhibitor should have preferable benefit-risk profile in comparison with pan-HDAC inhibitor. Finally, the HDAC8 selectivity of 12a, 12b and 12c was rationalized by molecular docking study.
在过去十年中，尽管组蛋白去乙酰化酶（HDAC）抑制剂作为治疗药物的研发取得了巨大成就，尤其是在肿瘤学领域，但考虑到非选择性HDAC抑制剂所引起的副作用，仍迫切需要发现亚型选择性HDAC抑制剂。HDAC8是一种独特的I类锌依赖性HDAC，正成为癌症和其他疾病的潜在靶点。在本研究中，设计并合成了一系列新型的基于N-羟基-3-氨磺酰基苯甲酰胺的HDAC8选择性抑制剂（12a - 12p），其中化合物12a、12b和12c表现出对HDAC8的强效抑制作用，IC值为两位数纳摩尔，并且通过蛋白质免疫印迹分析证实，它们对HDAC2（>180倍）和HDAC6（约30倍）具有相当高的选择性。值得注意的是，12a、12b和12c对T细胞白血病细胞系Jurkat、Molt - 4和神经母细胞瘤细胞系SK - N - BE - (2)显示出高度选择性的抗增殖活性。在著名的HDAC8选择性抑制剂PCI - 34051中也观察到了这种选择性细胞毒性，但在泛HDAC抑制剂SAHA和PXD101中未观察到，这表明与泛HDAC抑制剂相比，HDAC8选择性抑制剂应具有更好的效益风险比。最后，通过分子对接研究阐明了12a、12b和12c对HDAC8的选择性。
