Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed AKT phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor.

同时抑制 PI3K和 HDAC 已显示出治疗各种癌症的前景，导致其双重抑制剂作为新型抗癌药物的发现和开发。在此，我们公开了一系列新的PI3K/HDAC双重抑制剂，其带有苯甲酰胺部分作为HDAC抑制的药效基团。基于系统的构效关系研究，分别具有烷基和苯甲酰基连接基的化合物36和51被鉴定为具有良好的抗 PI3K 和 HDAC 功效。在细胞测定中，相对于单靶点抑制剂，化合物36和51对各种癌细胞系的抗增殖活性显着增强。此外，蛋白质印迹分析显示化合物36和51抑制MV4-11细胞中的AKT磷酸化并增加H3乙酰化，而流式细胞术分析显示这两种化合物剂量依赖性地诱导细胞周期停滞和细胞凋亡。在药代动力学研究的支持下，化合物36和51在 MV4-11 异种移植模型中进行了体内评估，证明了显着且剂量依赖性的抗癌功效。总体而言，这项工作通过使用双重抑制剂同时抑制 PI3K 和 HDAC 为治疗 AML 提供了一种有前景的方法。