Wang Yunfei, Stowe Ryan L, Pinello Christie E, Tian Guimei, Madoux Franck, Li Dawei, Zhao Lisa Y, Li Jian-Liang, Wang Yuren, Wang Yuan, Ma Haiching, Hodder Peter, Roush William R, Liao Daiqing
Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA; Department of Biochemistry and Molecular Biology, College of Life Sciences, Northwest Agriculture and Forestry University, Yangling, Shaanxi 712100, China.
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
Chem Biol. 2015 Feb 19;22(2):273-84. doi: 10.1016/j.chembiol.2014.12.015.
Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications.
组蛋白去乙酰化酶抑制剂（HDACi）作为临床抗癌疗法具有巨大的治疗潜力。然而，目前已知的HDACi表现出有限的亚型特异性、脱靶活性和不良的药物性质。因此，需要具有新化学类型的HDACi来克服这些限制。在此，我们鉴定出一类具有先前未描述的苯甲酰肼支架的HDACi，其对I类HDAC具有选择性。这些化合物是竞争性抑制剂，具有快速结合/缓慢解离的HDAC结合机制。我们表明，先导化合物UF010通过抑制I类HDAC来抑制癌细胞增殖。这导致蛋白质乙酰化和基因表达的全局变化，从而激活肿瘤抑制途径并同时抑制多种致癌途径。亚型选择性以及在抑制肿瘤细胞增殖方面有趣的生物学活性支持进一步对UF010类化合物进行临床前开发以用于潜在的治疗应用。
