Decernotinib is a selective JAK3 inhibitor with Ki value of 2.5nM, with >4-fold selectivity over JAK1, JAK2, and TYK2 with Ki values of 11nM, 13nM and 13nM, respectively.
Janus kinases (JAKs) includes cytokines, growth factors, and other chemical messengers rely on a class of intracellular nonreceptor tyrosine kinases can rapidly transduce intracellular signals. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. JAK3 is of particular interest due to its importance in immune function and its expression, which is largely confined to lymphocytes, thus limiting the potential impact of JAK3 inhibition on nonimmune physiology. JAK-STAT dysregulation results in autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn disease[3]. Decernotinib （VX-509） potently inhibits JAK3 in enzyme assays with Ki of 2.5 nM and cellular assays dependent on JAK3 activity with IC50 ranging from 50-170 nM. JAK3 inhibition by VX-509 was determined with an (interleukin) IL-2-induced STAT-5 phosphorylation assay in an IL-2-dependent T-cell line (HT-2). In the IL-2-stimulated HT-2-phosphorylated STAT-5 fluorescence-activated cell sorting assay, VX-509 had an IC50 of 99 ± 40 nM. VX-509 showed statistically significant, dose-dependent inhibition of the increases in ankle diameter and paw weight that occur in response to collagen injections in rats treated with VX-509 b.i.d. at doses of 10, 25, or 50 mg/kg or etanercept at 10 mg/kg. Inhibition of ankle diameter increase was significant with VX-509 at 10 mg/kg b.i.d. (55% inhibition), 25 mg/kg b.i.d. (70% inhibition), 50 mg/kg b.i.d. (76% inhibition), or 10 mg/kg etancercept (55% inhibition) relative to collagen plus vehicle-treated rats[4].
作用机制
Decernotinib can bind to ATP binding pockets of JAK2 with hinge hydrogen bonds
to Leu 932.
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