Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship.

Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC ₅₀  = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC ₅₀ value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC ₅₀ value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.
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