PI3Kδ is a lipid kinase mainly expressed in hematopoietic cells and responsible for key signal transduction in cells of the immune system. Antigens can acutely activate PI3Kδ in B and T cells. PI3Kδ controls lymphocyte development and differentiation through the AKT/FOXO1/mTOR pathway. On the other hand, it illustrates that PI3Kδ is a potential target in allergic and inflammatory diseases. Moreover, excessive activation of PI3Kδ leads to T cell senescence, death and impaired antibody response. Such gain-of-function mutations in PI3Kδ cause a primary immunodeficiency disorder, activated PI3Kδ syndrome (APDS; also known as PASLI disease). APDS usually exhibits characteristics with lymphoproliferative disorders and an increased B-cell malignancies risk. Therefore, PI3Kδ inhibition plays an important role in improving APDS as well as inflammatory and autoimmune diseases. Here we introduce a potent PI3Kδ inhibitor, Leniolisib (CDZ173).

Leniolisib is an orally active PI3Kδ inhibitor to inhibit arthritis model.

Specifically, Leniolisib broadly inhibits PI3Kδ-dependent immune cell functions in humans, macaques, rats, and mice, with IC₅₀s for inhibiting T cells and B cells in vitro of 7 nM-0.2 μM. It (100 mg/kg; po; twice daily for 4 weeks) is able to maintain insulin stability in mice. CDZ173 (3-30 mg/kg; po; twice daily for 4 weeks) inhibits B-cell activation in rats and monkeys in vivo in a concentration- and time-dependent manner. In a collagen-induced rat arthritis model, CDZ173 significantly alleviates disease symptoms. Including inhibition of paw swelling, joint erosions, as well as inflammatory cell infiltration, and proteoglycan loss. In an ozone-induced mouse model of lung inflammation, it also inhibits the increase of neutrophils and macrophages number.

In conclusion, Leniolisib is a potent inhibitor of activated PI3Kδ syndrome, destructive to immune cell function. It effectively inhibits the production of antigen-specific antibodies and alleviates symptoms in rat arthritis model.

Reference:

[1] Hoegenauer K, et al. ACS Med Chem Lett. 2017 Aug 25;8(9):975-980.