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 (EC50 = 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 EC50 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 IC50 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.