Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

PI3K delta signaling promotes cancer proliferation. To model this interesting target, we collected 79 PI3K delta inhibitors of known bioactivities and divided them into four groups for pharmacophore modelling. Subsequent QSAR modelling (r(64)(2) = 0.82, r(LOO)(2) = 0.86, F = 51.92, and r(PRESS)(2) versus 15 test inhibitors = 0.90) identified two optimal orthogonal pharmacophores that were evaluated using ROC curve analysis. The pharmacophores were subsequently used to mine the National Cancer Institute's (NCI) chemical list for new anti-PI3K delta hits. Subsequent in vitro evaluation identified ten hits of IC50 values ranging from 4.2-51.1 mu M. Seven hits were found to be cytotoxic against A549 alveolar lung cancer cells. The most potent hit exhibited anti-PI3K delta IC50 of 4.1 mu M.