Leniolisib

Phosphoinositide-3-kinase δ (PI3Kδ) is a lipid kinase activated downstream of tyrosine kinase receptors and G-protein–coupled receptors in immune cells. It mediates the PI3K/AKT pathway, which is involved in cell proliferation, growth, and survival. A heterodimer made up of a regulatory subunit (p85α) and a catalytic subunit (p110δ), PI3Kδ is primarily expressed on hematopoietic cells such as lymphocytes and myeloid cells. It converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), a signalling molecule that downstream proteins like the AKT kinase, which activate mammalian target of rapamycin (mTOR) complex I and inhibit FOXO family of transcription factors. APDS is associated with gain-of-function variants in the gene encoding p110δ or loss of function variants in the gene encoding p85α, each causing hyperactivity of PI3K-delta, reduced T cell function, lymphadenopathy, and immunodeficiency.

Leniolisib inhibits PI3Kδ by blocking the active binding site in the p110δ subunit. In cell-free isolated enzyme assays, the selectivity was higher for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAKT pathway activity and inhibited proliferation and activation of B and T cell subsets. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and the dysregulation of B and T cells.