Discovery of Novel PI3Kδ Inhibitors Based on the p110δ Crystal Structure

PI3K delta is a key mediator of B-cell receptor signaling and plays an important role in the pathogenesis of certain hematological malignancies, such as chronic lymphocytic leukemia. Idelalisib, which targets PI3K delta specifically, is the first approved PI3K inhibitor for cancer therapy. Recently, we carried out virtual screening, cell-based assays, adapta kinase assays, and molecular dynamic analysis to discover novel PI3K delta inhibitors and identified NSC348884 as a lead PI3K delta inhibitor. NSC348884 had an excellent docking score, potent PI3K delta-inhibitory activity, antitumor effects on various cancer cell lines, and a favorable binding mode with the active site of PI3K delta. Moreover, through the structural modification of NSC348884, we further discovered comp#1, which forms H-bonds with both Val828 and Lys779 in the ATP binding pocket of PI3K delta, with a more favorable conformation binding to PI3K delta. In addition, we found that N-1, N-1, N-2-trimethyl-N-2-((6-methyl-1H-benzo[d]imidazol-2-yl) methyl) ethane-1,2-diamine might be a potential scaffold structure. Thus, the result of this study provides a far more efficient approach for discovering novel inhibitors targeting PI3K delta.