Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3K 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 PI3K 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 selective PI3K inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, seletalisib inhibited -formyl peptide-stimulated but not phorbol myristate acetate-stimulated superoxide release from human neutrophils, consistent with a PI3K-specific activity. No indications of cytotoxicity were observed in peripheral blood mononuclear cells (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. 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 in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Collectively, these data characterize seletalisib as a selective PI3K inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated proinflammatory cytokine secretion.
Apical sodium-bile acid transporter BCRP Breast Cancer Resistance Protein BLQ Below limit of quantitation CYP2C19 Cytochrome P450 Family 2 Subfamily C Member 19 CYP3A4 Cytochrome P450 Family 3 Subfamily A Member 4 CYP3A5 Cytochrome P450 Family 3 Subfamily A Member 5 DDA Data-dependent acquisition DME Drug metabolizing enzymes DT Drug transporter DTT Dithiothreitol EDTA Ethylenediaminetetraacetic acid ESI Electrospray ionization FA Formic acid FDR False discovery rate IAA Iodoacetamide IHC Immunohistochemistry LC-MS/MS Liquid chromatography with tandem mass spectrometry LLOQ Lower limit of quantitation MCT1 Monocarboxylate transporter 1 MDR1 Multidrug resistance protein 1 or P-glycoprotein MRM Multiple Reaction Monitoring mRNA Messenger RNA MRP2 Multidrug resistance-associated protein 2
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