Cytokines, growth factors, and other chemical messengers rely on a class of 
intracellular nonreceptor tyrosine kinases known as Janus kinases (JAKs) to 
rapidly transduce intracellular signals. A number of these cytokines are 
critical for lymphocyte development and mediating immune responses. 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. The aim of this study was to evaluate 
the potency and selectivity of the investigational JAK3 inhibitor VX-509 
(decernotinib) 
[(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide] 
against JAK3 kinase activity and inhibition of JAK3-mediated signaling in vitro 
and JAK3-dependent physiologic processes in vivo. These results demonstrate that 
VX-509 potently inhibits JAK3 in enzyme assays (Ki = 2.5 nM + 0.7 nM) and 
cellular assays dependent on JAK3 activity (IC50 range, 50-170 nM), with limited 
or no measurable potency against other JAK isotypes or non-JAK kinases. VX-509 
also showed activity in two animal models of aberrant immune function. VX-509 
treatment resulted in dose-dependent reduction in ankle swelling and paw weight 
and improved paw histopathology scores in the rat collagen-induced arthritis 
model. In a mouse model of oxazolone-induced delayed-type hypersensitivity, 
VX-509 reduced the T cell-mediated inflammatory response in skin. These findings 
demonstrate that VX-509 is a selective and potent inhibitor of JAK3 in vitro and 
modulates proinflammatory response in models of immune-mediated diseases, such 
as collagen-induced arthritis and delayed-type hypersensitivity. The data 
support evaluation of VX-509 for treatment of patients with autoimmune and 
inflammatory diseases such as rheumatoid arthritis.