Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3K inhibitors

The delta isoform of class I PI3K (PI3K delta) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3K delta (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 mu M). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3K delta, in concentrationdependent manner. In view of the significant improvement in potency of PI3K delta and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3K delta inhibitor.