Abstract：
Inhibition of PI3K and histone deacetylase (HDAC) activity simultaneously using a single molecule appears to be a promising approach for cancer treatment. Current PI3K/HDAC dual inhibitors commonly use hydroxamate moiety as zinc binding group, which lack HDAC isoform selectivity and have potential genotoxicity. In this study, a novel series of benzamide-based PI3K/HDAC dual inhibitors were rationally designed and synthesized. Representative compound PH14 showed potent inhibitory activity toward PI3Kα and HDAC3, with IC50 values of 20.3 nM and 24.5 nM, respectively. This was further supported by the blockage of AKT phosphorylation and an increase in acetylated histone H3 levels in Western blot study. The advantage of simultaneously targeting PI3Kα and HDAC is not only reflected in the significant antiproliferative activity, but also in its ability to promote the apoptosis in Jeko-1 cells. Moreover, PH14 had weak inhibitory effects on CYP450 enzymes and hERG. In the pharmacokinetic study, the administration of 1 mg/kg of PH14 the administration of 1 mg/kg of PH14 resulted in a t1/2 of 10 h and an AUC (0-∞) of 2772 h ng/mL. Our study may provide ideas for the further development of novel HDAC/PI3K dual inhibitors.
摘要：
使用单个分子同时抑制PI3K和组蛋白脱乙酰酶（HDAC）活性似乎是一种有希望的癌症治疗方法。目前的PI3K/HDAC双重抑制剂通常使用异羟肟酸部分作为锌结合基团，缺乏HDAC同工型选择性并具有潜在的遗传毒性。在这项研究中,合理设计和合成了一系列基于苯甲酰胺的PI3K/HDAC双重抑制剂。代表性化合物PH14对PI3Kα和HDAC3显示出有效的抑制活性，IC50值为20.3nM和24.5nM，分别。蛋白质印迹研究中AKT磷酸化的阻断和乙酰化组蛋白H3水平的增加进一步支持了这一点。同时靶向PI3Kα和HDAC的优势不仅体现在显著的抗增殖活性,而且还具有促进Jeko-1细胞凋亡的能力。此外，PH14对CYP450酶和hERG的抑制作用较弱。在药代动力学研究中，给予1mg/kg的PH14，给予1mg/kg的PH14导致10h的t1/2和2772hng/mL的AUC（0-∞）。本研究可为进一步开发新型HDAC/PI3K双重抑制剂提供思路。
