磷酸肌醇3-激酶（PI3K）是一种重要的细胞信号传导分子，而PI3Kα是癌症中突变最多的家族成员。选择性PI3Kα抑制剂近年来成为研究的热点，因其出色的疗效和降低的副作用。在这里，我们基于结构为1,3,5-三氮杂嗪或嘧啶骨架的苯甲酰肼，以基于构效关系的药物发现（SBDD）和计算机辅助药物设计（CADD）的策略，描述了一系列PI3Kα抑制剂的开发，以广谱PI3K抑制剂ZSTK474为基础。其中，化合物F8表现出改良的选择性PI3Kα抑制活性，IC50值为0.14 nM，并在PC-3细胞系（IC50 = 0.28 μM）、HCT-116细胞系（IC50 = 0.57 μM）和U87-MG细胞系（IC50 = 1.37 μM）中显示出更显著的抗增殖活性，相较于ZSTK-474。化合物F8以剂量依赖的方式引起U87-MG细胞中线粒体膜明显下降，导致细胞周期在G1期停滞并诱导凋亡。此外，在U87-MG细胞系的裸鼠移植瘤模型中，化合物F8显著抑制肿瘤生长，且经腹腔注射40 mg/kg后未见明显毒性。化合物F8可能作为PI3Kα选择性抑制剂，并为患者提供了避免与I类PI3K家族广泛抑制相关的副作用的机会。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Phosphoinositide 3-kinase (PI3K) was an important cellular signal transducer, while PI3Kα was the most mutated family member in cancer. Selective PI3Kα inhibitors have become the frequent research in recent years because of their excellent curative effect and reduced side effects. Here, we described a series of PI3Kα inhibitors with 1,3,5-triazine or pyrimidine skeleton containing benzoyl hydrazine based on the pan-PI3K inhibitor ZSTK474 relying on the strategies of structure-based drug discovery (SBDD) and computer-aided drug design (CADD). Among them, compound F8 exhibited improved selective PI3Kα inhibition with an IC50 value of 0.14 nM and more significant anti-proliferative activities against three tumor-derived cell lines (PC-3 IC50 = 0.28 μM, HCT-116 IC50 = 0.57 μM, and U87-MG IC50 = 1.37 μM) than ZSTK-474. Compound F-8 induced a great decrease in mitochondrial membrane which caused cell cycle arrest at G1 phase and apoptosis in U87-MG cells in a dose-dependent manner. Furthermore, compound F8 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line with no clear evidence of toxicity following intraperitoneal injection of 40 mg/kg. Compound F8 may serve as a PI3Kα-selective inhibitor and provided the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.Copyright © 2023 Elsevier Inc. All rights reserved.