Discovery of the Potent Phosphoinositide 3-Kinase δ (PI3 K δ) Inhibitors

The PI3K delta plays a pivotal role in regulating immune cell function and has recently emerged as a promising therapeutic target in treating various diseases, which draw more and more attention to discover potent PI3K delta inhibitors in recent years. Starting from structure-based drug design, a series of derivatives were designed and synthesized as new chemotypes of PI3K delta inhibitors. The potential compounds were structurally optimized by interaction showed in docking study. In cell-free kinase activity assays, Homogeneous Time-Resolved Fluorescence Assay (HTRF) method was performed for evaluating the inhibitory activities against PI3K delta. Interestingly, the representative compound 4 exhibited potent PI3K delta activity (IC50=72 nM), which is comparable to that of positive compound TGR1202. Furthermore, compound 4 showed 15-fold water solubility than TGR1202. In addition, the tests of compound 4 on anti-cancer activity against jeko-1 cancer cell line and cytotoxicity against peripheral blood mononuclear cell (PBMC) suggested high inhibition activity and low toxicity respectively. A series of experiments indicated that compound 4 possessed novel chemical structure and high-efficiency PI3K delta inhibition activity, deserving further structural optimization to develop highly potent PI3K delta inhibitors.