基于2-(二氟甲基)-1-[4,6-二(4-吗啉基)-1,3,5-三嗪-2-基]-1H-苯并咪唑(ZSTK474),已设计并合成了三个系列的新型1,3,5-三嗪或嘧啶衍生物,其中包含氨基脲酮,以获得新的有效和选择性的PI3Kα抑制剂。对PI3Kα和三种肿瘤来源的细胞系(U87-MG,MCF-7和PC-3)。我们还测试了其他PI3KI类亚型(PI3Kβ,PI3Kδ,和PI3Kγ)活性。代表性化合物A10对PI3Kα的IC50值为0.32nM,并表现出非凡的亚型选择性。此外,化合物A10明显抑制MCF-7细胞株的增殖,诱导线粒体膜电位的大幅下降,导致癌细胞凋亡,并以剂量依赖性方式阻止G2期。此外,化合物A10在U87-MG细胞系的异种移植小鼠模型中诱导显著的肿瘤消退,在20mg/kg口服给药后没有明显的毒性迹象。化合物A10可用作PI3Kα选择性抑制剂,并提供使患者免于与I类PI3K家族的更广泛抑制相关的副作用的机会。
Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing
semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kβ, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.