ABSTRACT
Las proteínas cinasas desempeñan un papel fundamental en las vías de señalización intracelular implicadas tanto en la proliferación celular como en la inflamación. El mejor conocimiento de estas vías metabólicas, y del mecanismo patogénico de las señales intracelulares de la psoriasis, está provocando el desarrollo e investigación de un nuevo grupo de fármacos en el tratamiento de esta enfermedad y de otros procesos inflamatorios. Los inhibidores de las cinasas son moléculas de pequeño tamaño que van a permitir un tratamiento vía oral o tópico. El futuro papel de estos fármacos dentro del arsenal terapéutico de la psoriasis está todavía por determinar, ya que la mayoría de moléculas están en fases precoces de investigación. Su hipotético coste inferior al de los tratamientos biológicos pudiera favorecer su aprobación en los próximos años. Tofacitinib, un inhibidor de las cinasas Janus, es el fármaco con investigación más avanzada y resultados prometedores (AU)
Protein kinases play a crucial role in the intracellular signaling pathways involved in inflammation and cell proliferation. Advances in our understanding of these metabolic pathways and of the role played by intracellular signaling in the pathogenesis of psoriasis have led to research in this area and the development of a new class of drugs for the treatment of psoriasis and other inflammatory processes. Since kinase inhibitors are small molecules, oral and topical treatments are possible. The future role of these molecules in the therapeutic arsenal used to treat psoriasis is as yet unknown because in most cases they are still in the early stages of research. The fact that these drugs may cost much less than biologic therapies could favor their approval in coming years. Tofacitinib, a Janus kinase inhibitor, is the drug that has reached the most advanced stage of research and has shown the most promising results (AU)
Subject(s)
Humans , Male , Female , Psoriasis/drug therapy , Phosphotransferases/antagonists & inhibitors , Phosphotransferases/therapeutic use , Cell Proliferation , Janus Kinases/classification , Janus Kinases/therapeutic use , Drug Hypersensitivity/epidemiology , Janus Kinases/metabolism , Mitogens/therapeutic useABSTRACT
BACKGROUND: Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK)-Signal transducer and activator of transcription (STAT) pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP), Protein inhibitors against Stats (PIAS), and Suppressor of cytokine signaling (SOCS) proteins across a diverse range of organisms. RESULTS: Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components. CONCLUSION: Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.
Subject(s)
Immune System/metabolism , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Animals , Evolution, Molecular , Humans , Janus Kinases/classification , Janus Kinases/genetics , Models, Biological , Phylogeny , Protein Inhibitors of Activated STAT/classification , Protein Inhibitors of Activated STAT/genetics , Protein Inhibitors of Activated STAT/metabolism , Receptors, Cytoplasmic and Nuclear/classification , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , STAT Transcription Factors/classification , STAT Transcription Factors/genetics , Suppressor of Cytokine Signaling Proteins/classification , Suppressor of Cytokine Signaling Proteins/genetics , Suppressor of Cytokine Signaling Proteins/metabolism , SyntenyABSTRACT
There are four members of the JAK family of protein tyrosine kinases (PTKs) in the human genome. Since their discovery in 1989, great strides have been made in the understanding of their role in normal intracellular signalling. Importantly, their roles in pathologies ranging from cancer to immune deficiencies have placed them front and centre as potential drug targets. The recent discovery of the role of activating mutations in the kinase-like domain (KLD) of JAK2 in the development of polycythemia rubra vera, and the elaboration of KLD mutation as a broader mechanism by which cells might become hyperproliferative has sparked enormous interest in the development of JAK selective drug candidates. I review herein the progress that has been made in the discovery of JAK-targeted inhibitors, and discuss the challenges that face the development of these drugs for use in the clinic.
