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 t_1/2 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.

使用单个分子同时抑制 PI3K 和组蛋白脱乙酰酶 (HDAC) 活性似乎是一种有前途的癌症治疗方法。目前的PI3K/HDAC双重抑制剂普遍采用异羟肟酸部分作为锌结合基团，缺乏HDAC异构体选择性，且具有潜在的基因毒性。本研究合理设计并合成了一系列新型的基于苯甲酰胺的PI3K/HDAC双重抑制剂。代表性化合物PH14对PI3Kα和HDAC3表现出有效的抑制活性，IC ₅₀值分别为20.3 nM和24.5 nM。Western blot 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着的抗增殖活性，还体现在其促进Jeko-1细胞凋亡的能力。此外，PH14对CYP450酶和hERG有较弱的抑制作用。在药代动力学研究中，给予 1 mg/kg PH14给予 1 mg/kg PH14 导致10 h 的_1/2和 AUC _(0-∞)为 2772 h ng/mL。我们的研究可能为新型HDAC/PI3K双重抑制剂的进一步开发提供思路。