Decernotinib

Uses

Decernotinib is a potent and selective Janus kinase 3 inhibitor for treatment of autoimmune diseases.

Biological Activity

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].

in vivo

IC 50

JAK3: 2.5 nM (Ki); JAK1: 11 nM (Ki); Tyk2: 11 nM (Ki); JAK2: 13 nM (Ki); FLT3: 1 μM (Ki); ROCK I: 1.5 μM (Ki); GSK3β: 1.8 μM (Ki); CDK2/CycA: 2.6 μM (Ki); PknB: 8 μM (IC₅₀)

References

[1]. farmer lj, ledeboer mw, hoock t, et al. discovery of vx-509 (decernotinib): a potent and selective janus kinase 3 inhibitor for the treatment of autoimmune diseases. j med chem, 2015, 58(18): 7195-7216.
[2]. mahajan s, hogan jk, shlyakhter d, et al. vx-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. j pharmacol exp ther, 2015, 353(2): 405-414.