PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances.PI3Kδ has been validated as a promising target for cancer therapy,and specific PI3Kδ inhibitors were approved for clinical practice.However,the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma(DLBCL)limit their clinical use.In this study,we described a novel PI3Kδ inhibitor SAF-248,which exhibited high selectivity for PI3Kδ(IC50=30.6 nM)over other PI3K isoforms at both molecular and cellular levels,while sparing most of the other human protein kinases in the kinome profiling.SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδinhibitor idelalisib.In particular,SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines(with Gl50 values＜1 μM in 5 DLBCL cell lines).We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G,phase arrest and apoptosis in DLBCL KARPAS-422,Pfeiffer and TMD8 cells.Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα.Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells.Activation of mTORC1,MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248.Taken together,SAF-248 is a promising selective PI3Kδinhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.