Abstract
PI3Ks are key signaling enzymes regulating cellular survival, development and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small molecule inhibitor of PI3Kδ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive and highly selective PI3Kδ inhibitor able to block AKT phosphorylation following activation of the BCR in a B-cell line. Moreover, seletalisib inhibited N-formyl peptides (fMLP)-stimulated but not phorbol myristate acetate (PMA)-stimulated superoxide release from human neutrophils consistent with a PI3Kδ-specific activity. No indications of cytotoxicity were observed in PBMCs or other cell types treated with seletalisib. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Seletalisib inhibited T-cell differentiation to Th1, Th2, and Th17 subtypes..Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib showed dose-dependent inhibition of in vivo model of anti-CD3-antibody-induced IL-2 release. Collectively, these data characterize seletalisib as a highly-selective PI3Kδ inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated pro-inflammatory cytokine secretion.
- The American Society for Pharmacology and Experimental Therapeutics