Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases

While several therapeutic
options exist, the need for more effective,
safe, and convenient treatment for a variety of autoimmune diseases
persists. 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. We screened our compound library against JAK3,
a key signaling kinase in immune cells, and identified multiple scaffolds
showing good inhibitory activity for this kinase. A particular scaffold
of interest, the 1H-pyrrolo­[2,3-b]­pyridine series (7-azaindoles), was selected for further optimization
in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this
chemical series led to the identification of VX-509 (decernotinib),
a novel, potent, and selective JAK3 inhibitor, which demonstrates
good efficacy in vivo in the rat host versus graft model (HvG). On
the basis of these findings, it appears that VX-509 offers potential
for the treatment of a variety of autoimmune diseases.