Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3Kδ

Abstract

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.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

“…The reductions in collagen antibody in the CIA model are consistent with the role of PI3Kδ (>PI3Kγ) on B cell function and/or T: B cross talk, and with its effects on IgG production in T/B cocultures in vitro (BioMap™ assay). The attenuation of IgG production by seletalisib, a PI3Kδ selective inhibitor, in BioMAP™ T:B cocultures further supports the role of PI3Kδ in T:B cross talk.…”

“…Consistent with the known PI3Kδ/PI3Kγ biology, HM5023507 modulated diverse immune responses such as activation of innate and adaptive immune cells, markers of myeloid cell migration, cytokine secretion, and differentiation of naïve T cells into T‐helper cells. HM5023507 was equally potent in blocking the production of Th17 cytokines such as IL‐17A, IL‐22, and IFNγ in blood from healthy subjects and rheumatoid arthritis patients suggesting that its pharmacology was not significantly skewed by the disease setting.…”

“…In in vitro assays, HM5023507: (a) is a dual inhibitor of PI3Kδ and PI3Kγ isoforms with selectivity against other members of class I PI3K (PI3Kα and PI3Kβ) or class II/III isoforms and broad kinome selectivity, minimal off-target activity in ion-channel and GPCR screening, (b) inhibits PI3Kγ and PI3Kδ isoforms in isolated immune cells and in complex milieu such as the blood, and (c) attenuates T cell and B cell activation. The overall selectivity profile of HM5023507 allowed us to associate its pharmacology as on-target (PI3Kδ/γ) driven.Consistent with the known PI3Kδ/PI3Kγ biology,10,11,13,30,38 HM5023507 modulated diverse immune responses such as activation of innate and adaptive immune cells, markers of myeloid cell migration, cytokine secretion, and differentiation of naïve T cells into T-helper cells. HM5023507 was equally potent in blocking the production of Th17 cytokines such as IL-17A, IL-22, and IFNγ in blood from healthy subjects and rheumatoid arthritis patients suggesting that its pharmacology was not significantly skewed by the disease setting.…”

“…The lipid kinases (PI3Kα, β, γ, and δ are involved in diverse cellular functions such as cell growth, proliferation, differentiation, motility, survival, and trafficking and have been targeted extensively for drug discovery to treat cancer, autoimmune, and inflammatory diseases . These efforts have focused initially on pan‐PI3K inhibitors, and subsequently on isoform‐selective and dual isoform inhibitors . Nearly 15 compounds of varying PI3K isoform selectivity have been explored in the clinic culminating in the launch of four drugs to treat different forms of cancers: idelalisib [Zylidig®, a PI3Kδ selective inhibitor],] duvelisib [Copiktra®, a dual PI3Kδγ inhibitor], alpelsib [Piqray®, a PI3Kα inhibitor], and copanlisib [Aliqopa®,BAY 80‐6946, a dual PI3Kδα inhibitor] …”

“…[1][2][3][4][5][6][7][8][9] These efforts have focused initially on pan-PI3K inhibitors, and subsequently on isoform-selective and dual isoform inhibitors. 8,[10][11][12][13] Nearly 15 compounds of varying PI3K isoform selectivity have been explored in the clinic culminating in the launch of four drugs to treat different forms of cancers: idelalisib [Zylidig®, a PI3Kδ selective inhibitor], 5 ] duvelisib [Copiktra®, a dual PI3Kδγ inhibitor], 14 alpelsib [Piqray®, a PI3Kα inhibitor], 15 and copanlisib [Aliqopa®,BAY 80-6946, a dual PI3Kδα inhibitor]. 16 Dual inhibitors of PI3Kδ and PI3Kγ are considered high-value targets both for inflammation/ autoimmunity and oncology.…”