Oncogenic mutation H1047R in phosphatidylinositol 3-kinase alpha (PI3Ka) observed in many tumors may enhance its kinase activity by affecting loop confirmations. We investigated the binding affinity of PI3K inhibitors against the wild type PI3Ka, the H1047R mutant of PI3Ka and the ? isoform of PI3K (PI3K?). Our studies suggested that Gln859, Ser854 and Ser774 may play critical roles in ligand binding to the H1047R mutant while Ser806 of PI3K? may enhance ?-isoform-specific inhibition. In addition, structural and size differences in the activation and hydrophobic domains of these three proteins could be exploited to direct the design of isoform- and/or mutant-specific PI3K inhibitors. A pharmacophore model was built based on PI3Ka selective compounds. Three structurally diverse compounds were identified as inhibitors against the wt and the H1047R mutant. Further optimization of lead compounds have been carried out and biological activities of the synthesized compounds exhibited certain degree of mutant-selective binding.

Design, synthesis, and docking studies of phosphatidylinositol 3-kinase alpha inhibitors

244th National Meeting (2012)

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