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.

VX-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease.

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.

A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and safety of oral decernotinib (VX-509; Vertex Pharmaceuticals) monotherapy in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study of patients with rheumatoid arthritis (RA). METHODS: Two hundred four adults with active RA who had been unsuccessfully treated with ≥1 disease-modifying antirheumatic drug were administered placebo tablets or decernotinib twice a day at dosages of 25 mg, 50 mg, 100 mg, or 150 mg. Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and mean change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). RESULTS: At week 12, the ACR20 response rates were 39.0%, 61.0%, 65.0%, and 65.9% in the 25-mg, 50-mg, 100-mg, and 150-mg groups, respectively, and were significantly higher in the 50-mg group (P = 0.007) and the 100-mg and 150-mg groups (P = 0.002) as compared to the response rates in the placebo group (29.3%). The mean change from baseline in DAS28-CRP was greater in the 50-mg, 100-mg, and 150-mg groups as compared to the placebo group (P < 0.001). Decernotinib treatment resulted in higher ACR50 and ACR70 response rates, more patients with DAS28-CRP scores <2.6, and improvements in the Health Assessment Questionnaire disability index as compared to placebo. The most common adverse events in any decernotinib group were nausea (6.1%), headache (4.3%), an increase in levels of alanine aminotransferase (4.3%), and hypercholesterolemia (3.7%). In the groups receiving decernotinib, there was an increased risk of infections and increased liver transaminase levels. CONCLUSION: Decernotinib was efficacious in improving clinical signs and symptoms of RA at week 12 at dosages of 50-150 mg twice a day. Infections and increases in liver transaminase and lipid levels were noted as potential safety signals.

Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole.

The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK).

A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar K(i)'s against SYK and potent inhibition in mast cell degranulation assays.