Structure-based drug design, synthesis, and biological evaluation of novel 1,3,5-triazine or pyrimidine derivatives containing benzoyl hydrazine moiety as PI3Kα selective inhibitors

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.

Antitumor; Benzoyl hydrazine; Kinase selectivity; PI3-kinase; Synthesis.