Abstract

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC₅₀ values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC₅₀ value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells.

摘要

组蛋白去乙酰化酶 (HDAC) 是表观遗传学中开发抗癌药物的有效靶点。在发现具有抗癌效力的新型 HDAC 抑制剂时，5-氯-4-((取代的苯基)氨基)嘧啶片段作为帽基组装到 HDAC 抑制剂的结构中。SAR显示小基团的存在（例如甲氧基取代）有利于HDAC抑制活性。在酶抑制选择性测试中，化合物L20表现出 I 类选择性，对 HDAC1 的 IC ₅₀值为 0.684 µM（选择性指数 >1462）、2.548 µM（选择性指数 >392）和 0.217 µM（选择性指数 >4608） , HDAC2 和 HDAC3 与针对 HDAC6 的效力比较 (IC ₅₀值 > 1000 µM），分别。在抗增殖试验中，化合物L20显示出血液学和实体癌抑制活性。在流式细胞仪中，L20促进了K562细胞的G0/G1期细胞周期阻滞和凋亡。