SAF-248, a novel PI3Kδ-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma

PI3K delta is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3K delta has been validated as a promising target for cancer therapy, and specific PI3K delta 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 PI3K delta inhibitor SAF-248, which exhibited high selectivity for PI3K delta (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 PI3K delta inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI(50) values < 1 mu M in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G(1) 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 PI3K alpha. 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 PI3K delta inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.

Automated summary

The novel PI3K delta inhibitor SAF-248 exhibits high selectivity for PI3K delta and superior antiproliferative activity against DLBCL cells. It induces cell apoptosis by blocking PI3K signaling and shows dose-dependent inhibition of xenograft growth. Co-targeting mTORC1, MYC, and JAK/STAT signaling pathways enhances SAF-248's activity, making it a promising treatment option for DLBCL.