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Decernotinib(VX-509)is a novel, potent and selective inhibitor of JAK3 with Ki value of 2 nM [1].

The Janus kinase family consists of four members: JAK1, JAK2, JAK3, and TYK2. Janus kinase 3 (JAK3) is mainly expressed in lymphocytes, which are cells important to the immune response associated with many diseases, including rheumatoid arthritis (RA) [1].

Decernotinib(VX-509)is a novel, potent, selective and orally available JAK3 inhibitor for the treatment of autoimmune diseases. VX-509 inhibited JAK1, JAK2, JAK3, and TYK2 with Ki values of 11, 13, 2 and 11 nM, respectively. In HT-2 or TF-1 cells, VX-509 inhibited JAK3/1- or JAK2-mediated phosphorylation of STAT5 following stimulation with IL-2 or GMCSF with IC50 values of 99 and 2600 nM, respectively [1].

In the rat host versus graft (HvG) model, VX-509 at 50 mg/kg bid or 100 mg/kg qd significantly and dose-dependently inhibited popletial lymph node (PLN) hyperplasia by 66% and 94%, respectively, relative to cyclosporin A (CsA). VX-509 also significantly reduced CD25 expression. These results suggested that VX-509 showed significant dose-dependent immunosuppressive activity and effectively inhibited T-cell activation [1]. In the rat collagen-induced arthritis model, VX-509 dose-dependently reduced ankle swelling and paw weight, and improved paw histopathology scores. In oxazolone-induced delayed-type hypersensitivity mouse model, VX-509 reduced the T cell-mediated inflammatory response in skin [2].

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