In mature lymphocytes, the Spatio-temporal regulation of Ca2+ modulates signaling pathways. They serve to control a variety of cellular responses, such as activation, differentiation, effector function, and cell death. Thus, targeting kinases involved in Ca2+ responses is an attractive approach to treat immune disorders. But, people incompletely understand the components and mechanisms by Ca2+. The soluble second messenger, IP3, can be further phosphorylated by inositol kinases into higher-order inositol phosphates. The Ca2+-dependent kinase, inositol trisphosphate 3’ kinase B (Itpkb), phosphorylates the 3’ position of Ins(1,4,5)P3 to generate inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]. Thus, in addition to playing a critical role in lymphocyte development, Itpkb is required for mature T cell survival. GNF362 is a selective, potent, and orally bioavailable inhibitor of Itpkb (IC50=9 nM). It reveals a novel strategy to treat autoimmune disease.
GNF362 binds to the ATP-binding pocket of Itpkb. It also potently inhibits Itpka, as well as Itpkc. But it has no activity against a panel of more than 150 protein or lipid kinases. GNF362 specifically blocks Ins(1,3,4,5)P4 production but has no impact on Ins(1,4,5)P3 production. GNF362 blocks T cell proliferation upon anti-CD3/28 stimulation, and the presence of a blocking anti-FasL antibody reverses this effect. Therefore, GNF362 enhances FasL-mediated T cell death upon T cell activation. Blockade of Itpkb by GNF362 could serve as a suitable therapy for rheumatoid arthritis by blocking T cell-mediated inflammation and autoantibody responses. Thus, GNF362 blocks T cell-driven autoimmune disease.
In summary, GNF362 is a selective LMW Itpkb inhibitor, and it not only recapitulates Itpkb-deficiency both in vitro and in vivo but blocks disease in a rat model of arthritis. Itpkb may serve as a suitable target for T cell-mediated autoimmune disease.