SLE is a complex autoimmune inflammatory disease that affects multiple organs with unpredictable flares. Autoantibody/antigen immune-complexes in turn can activate TLR7 and/or TLR9 in plasmacytoid dendritic cells (pDCs) leading to the production of IFNα. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. PI3Kδ is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. PI3Ks, comprising α, β, γ, and δ isoforms, are fundamental components of cell signaling as they generate phosphatidylinositol (3,4,5)-triphosphate at the plasma membrane. It recruits and activates proteins containing phospholipid-binding domains, such as Akt, to initiate downstream signaling events leading to cell growth, survival, differentiation, proliferation, migration, or cytokine release. MSC2360844 is a potent, orally active, and selective PI3Kδ inhibitor, with an IC₅₀ of 145 nM. It shows highly selective against a panel of 278 additional kinases.

MSC2360844 is an orally active, and selective PI3Kδ inhibitor, with an IC₅₀ of 145 nM.

In an IFNα-accelerated NZB/WF1 SLE model, MSC2360844 blocks the development of proteinuria and kidney damage in a dose-dependent manner.  MSC2360844 completely abolishes BCR-induced pAkt in Ramos B cells in a concentration-dependent manner with IC₅₀ values of 280 nM. Moreover, MSC2360844 inhibits SLE-prone functions of human primary cells. MSC2360844 inhibits B cell proliferation in a concentration-dependent manner with an IC₅₀ of 7 nM.  In addition, MSC2360844 reduces TNFα, IL-6, and IL-10 with potencies similar to those observed in the B cell proliferation assay. It blocks B cell function effectively. MSC2360844 also inhibits PI3Kδ-mediated functions in SLE relevant subsets of primary human cells. Furthermore, it blocks PI3Kδ-mediated early B cell activation in peripheral blood from healthy donors in a concentration-dependent manner. MSC2360844 also ameliorates disease manifestations in a murine SLE model.

In summary, MSC2360844 blocks the development of proteinuria and kidney damage in a dose-dependent manner.

Reference:

Haselmayer P, et al. Front Immunol. 2014 May 22;5:233.