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

Farmer, Luc J.; Ledeboer, Mark W.; Hoock, Thomas; Arnost, Michael; Bethiel, Randy S.; Bennani, Youssef L.; Black, James; Brummel, Christopher L.; Chakilam, Ananthsrinivas; Dorsch, Warren A.; Fan, Bin; Cochran, John E.; Halas, Summer; Harrington, Edmund; Hogan, James K.; Howe, David; Huang, Hui; Jacobs, Dylan; Laitinen, Leena; Liao, Simeng; Mahajan, Sudipta; Marone, Valerie; Martínez-Botella, Gabriel; McCarthy, Pamela; Messersmith, David; Namchuk, Mark; Oh, Luke S.; Penney, Marina; Pierce, Albert C.; Raybuck, Scott A.; Rugg, Arthur; Salituro, Francesco G.; Saxena, Kumkum; Shannon, Dean; Shlyakter, Dina; Swenson, Lora; Tian, Shi‐Kai; Town, Christopher; Wang, Jian; Wang, Tiansheng; Wannamaker, M. W.; Winquist, Raymond J.; Zuccola, Harmon

doi:10.1021/acs.jmedchem.5b00301

Cited by 78 publications

(34 citation statements)

References 45 publications

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“…One example is the increase in cholesterol levels by tofacitinib, which is likely a result of reduced IL‐6 signaling , the other is the frequent development of anemia or thrombocytopenia by ruxolitinib, due to reduced erythropoietin and thrombopoietin signaling, respectively . A second generation of selective JAKi that targets individual JAKs is currently in development . Ongoing and future clinical trials will show if these more selective second generation JAKi have a comparable efficacy as the JAKi of the first generation, and at the same time more acceptable toxicities.…”

Section: Future Developments and Conclusionmentioning

confidence: 99%

Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors

et al. 2017

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For most inflammatory skin diseases topical glucocorticosteroids and traditional oral immunosuppressive drugs remain the principle treatment choices, but this has started to change. A deeper understanding in individual disease pathogenesis, basic immune mechanisms and molecular signalling pathways, together with advances in pharmaceutical drug development, allow us to interfere more precisely with disease-related factors. Some examples of inflammation-controlling interventions include antibodies neutralizing disease-associated cytokines, and small molecules targeting intracellular pathways relevant to cytokine production or cytokine signalling. So far, this is best established for psoriasis, an inflammatory skin disease dominated by Th17 cytokines. In this review, we focus on chronic inflammatory skin diseases where cytokines using type I/II cytokine receptors play a dominant role in disease pathogenesis and where novel treatments with inhibitors of the JAK/STAT pathway are already under clinical investigation. To better understand the rationale of using JAK/STAT inhibitors in the discussed skin diseases, we give an overview of important genetic and immunological associations with the JAK/STAT pathway and summarize the stage of clinical development of small molecular inhibitors. JAK/STAT inhibitors will presumably find wide application in dermatology, since they can be applied not only systematically but also topically for the treatment of inflammatory skin diseases.

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Section: Future Developments and Conclusionmentioning

confidence: 99%

Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors

et al. 2017

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“…There has been growing interest in developing highly selective JAK3 inhibitors to combat inflammation with minimal side effects (9, 10). JAK3 inhibition has been shown to be efficacious at ameliorating inflammation in a multitude of diseases (10–12).…”

Section: Introductionmentioning

confidence: 99%

“…JAK3 inhibition has been shown to be efficacious at ameliorating inflammation in a multitude of diseases (10–12). Decernotinib (VX-509) inhibits JAK3-mediated signaling both in vitro and in vivo with a high potency and selectivity and is clinically used to treat rheumatoid arthritis (9, 10). …”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Janus Kinase 3 Has No Impact on Infarct Size or Neurobehavioral Outcomes in Permanent Ischemic Stroke in Mice

et al. 2017

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Janus kinase 3 (JAK3) is associated with the common gamma chain of several interleukin (IL) receptors essential to inflammatory signaling. To study the potential role of JAK3 in stroke-induced neuroinflammation, we subjected mice to permanent middle cerebral artery occlusion and investigated the effects of JAK3 inhibition with decernotinib (VX-509) on infarct size, behavior, and levels of several inflammatory mediators. Results from our double immunofluorescence staining showed JAK3 expression on neurons, endothelial cells, and microglia/macrophages in the ischemic mouse brain (n = 3). We found for the first time that total and phosphorylated/activated JAK3 are dramatically increased after stroke in the ipsilateral hemisphere (**P < 0.01; n = 5–13/group) in addition to increased IL-21 expression after stroke (**P < 0.01; n = 5–7/group). However, inhibition of JAK3 confirmed by reduced phosphorylation of its activation loop at tyrosine residues 980/981 does not reduce infarct volume measured at 48 h after stroke (n = 6–10/group) nor does it alter behavioral outcomes sensitive to neurological deficits or stroke-induced neuroinflammatory response (n = 9–10/group). These results do not support a detrimental role for JAK3 in acute neuroinflammation following permanent focal cerebral ischemia. The functional role of increased JAK3 activation after stroke remains to be further investigated.

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“…1) was evaluated for anti-HIV-1 activity. This versatile scaffold is a biostere of natural purines 5 and the motif is found in investigational drugs targeting the influenza virus, 6 autoimmune disorders, 7 and cancer. 8 The library tested here included 585 compounds with a variety of substitutions off of six positions on the core (Fig.…”

mentioning

confidence: 99%

Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors

Stanton

Detorio

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5μM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.

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

Cited by 78 publications

References 45 publications

Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors

Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors

Selective Inhibition of Janus Kinase 3 Has No Impact on Infarct Size or Neurobehavioral Outcomes in Permanent Ischemic Stroke in Mice

Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors

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