April 2014

Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors

Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279

Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...

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Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis

. ARD published online first 13 Feb 2014. Doi: 10.1136/annrheumdis-2013-204105

Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3...

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November 2013

Terapéutica dirigida a la vía de la JAK/STAT

Basic Clin Pharmacol Toxicol. 2013 Oct 24. doi: 10.1111/bcpt.12164

The inhibition of the JAK/STAT pathway has proven to be a powerful therapeutic tool in the treatment of autoimmune diseases. The authors review the role of the JAK/STAT pathway in human disease, including the role of mutations in defective function of this pathway. They discuss the rationale behind JAK inhibition and review the two JAK inhibitors currently approved by the FDA for clinical use; tofacitinib, for the treatment of RA, and ruxolitinib, for the treatment of polycythaemia vera and myel...

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October 2013

Participación de la señalización JAK/STAT en la patogénesis de la enfermedad intestinal inflamatoria

Pharmacological Research 2013; 76:1–8

The JAK/STAT signalling pathway has been implicated in the pathogenesis of several inflammatory diseases including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). In this review, Coskun et al. provide an excellent background overview of the JAK/STAT cascade. They also highlight recent study findings investigating the mechanisms of the JAK/STAT pathway and the anti-inflammatory effects of novel JAK inhibitors in development and in clinical trials, particularly in IBD. In one study...

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Caracterización preclínica de GLPG0634, un inhibidor selectivo de la JAK1, para el tratamiento de las enfermedades inflamatorias

Journal of Immunology 2013;191:3568–77

JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...

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Inhibición de la vía de señalización JAK/STAT en fibroblastos sinoviales reumatoides utilizando compuestos de moléculas pequeñas

Clin Exp Immunol. 2013 Aug 23. doi: 10.1111/cei.12190

Current JAK inhibitors CP-690,550 and INCB020850 have inhibitory effects on multiple JAK pathways, therefore Migita et al. tested whether selective inhibition of JAK3, using PF-956980, would be enough to ameliorate the rheumatoid inflammatory process. The results indicated that the inhibition of JAK3 alone is does not achieve control of STAT3-dependent signalling, and while it is suggested that the targeting of singular JAK pathways should lead to fewer adverse events, it appears that this appro...

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August 2013

El inhibidor de la JAK tofacitinib para la artritis reumatoide: resultados de estudios de fase III

International Journal of Clinical Rheumatology June 2013; 8(3):311–13

The tofacitinib ORAL research program involves six phase 3 trials (Standard, Solo, Step, Scan, Sync and Start) to assess the safety and efficacy of tofacitinib 5 and 10 mg twice daily as monotherapy, or with either background MTX or traditional DMARD therapy. This report by Salgado et al. provides an overall analysis of the each of the study designs and the clinical results to date. The results show that tofacitinib effectively controlled the signs and symptoms of RA across a range of patient po...

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June 2013

Moléculas pequeñas dirigidas a JAKs – un nuevo método en el tratamiento de la artritis reumatoide

Rheumatology 2013: doi: 10.1093/rheumatology/kes417

This article focuses on the development of new small molecular inhibitors of Janus kinases (Jaks) in clinical trials for rheumatoid arthritis (RA). Of these, tofacitinib is at the most advanced stage of its clinical development and this article includes an overview of the results from the main tofacitinib clinical trials to date. These include the ORAL-Start study in methotrexate (MTX)-naïve patients; ORAL-Scan in inadequate responders to MTX; ORAL-Solo and ORAL-Sync in inadequate responders to ...

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Inhibidores de la quinasa de Janus en la enfermedad autoinmune

Annals of the Rheumatic Diseases 2013; 72:ii111-ii115

This review describes the role of various cytokines in rheumatoid arthritis (RA) and related diseases. This includes an overview of the different types of cytokine receptors including type I, which bind some of the interleukins (ILs), colony stimulating factors (CSFs) and hormones such as erythropoietin, prolactin and growth hormone (GH); and type II, which bind to interferons and IL-10-related proteins. In addition, the cytoplasmic domain of type I and II cytokine receptors bind to members of a...

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Modulación de respuestas inmunes innatas y adaptativas mediante tofacitinib (CP-690,550)

Journal of Immunology 2011; 186(7):4234-43

This study investigated the effects of the novel Janus kinase (JAK) inhibitor CP-690,550 (now known as tofacitinib) on adaptive and innate immune responses, in order to establish the mode of action of JAK inhibitors in the setting of inflammatory diseases. The inhibition of specific JAK/STAT-dependent pathways by CP-690,550 was determined through analysis of cytokine stimulation of mouse and human T cells in vitro.The effects of CP-690,550 on Th-cell differentiation of naive murine CD4+...

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