Based on 2-(difluoromethyl)-1-[4,6-di (4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors

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 PI3K alpha inhibitors. Their inhibitory activities in vitro were eval-uated against PI3K alpha 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 (PI3K beta, PI3K delta, and PI3K gamma) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3K alpha, 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 PI3K alpha-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.

Automated summary

In this study, novel semicarbazone derivatives were designed and synthesized to be potent and selective PI3K alpha inhibitors. Compound A10 showed extraordinary selectivity and inhibition activity against PI3K alpha, and demonstrated significant anticancer effects in both cell and animal models.