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News Article | November 12, 2016
Site: www.sciencedaily.com

University of Tübingen researchers have developed new inhibitors which act on a special enzyme known as the Janus kinase 3 (JAK3). Janus kinases carry out important intracellular functions in many organs -- for instance, activating key signal pathways in the systems which form new blood cells. But mutations in Janus kinase genes can cause alterations in these processes, leading to a number of blood and immune diseases. Because many cytokines use Janus kinases to carry their signals during inflammation, these molecules also play a major role in inflammatory autoimmune disorders such as rheumatoid arthritis and psoriasis. If researchers can inhibit the function of Janus kinases, they may be able to find better treatments for a number of diseases. The researchers have published their findings in the latest edition of Cell Chemical Biology. "For ten years, medicine has been looking for the right inhibitors to control the effect of JAK3," says Stefan Laufer, Professor of Pharmaceutical Chemistry at the University of Tübingen. "Because JAK3 has such an isolated role in the immune system, we believe that inhibiting it will lead to a suppression of immune responses which could be used to treat autoimmune disorders like psoriasis and rheumatoid arthritis. All the agents which are currently available -- and have been approved as medication in some countries -- inhibit several Janus kinases at the same time." That may be the cause of undesirable side effects observed in patients treated with JAK inhibitors. The JAK inhibitors developed in Tübingen exploit small differences in the amino acid sequences of the four types of Janus kinases. They bond with a cysteine amino acid which only occurs in JAK3 -- thereby blocking this enzyme but not the other Janus kinases. "There are more than 500 kinases in the human body; and many of them are essential building-blocks of life," Laufer explains. "So it is of vital importance that a JAK inhibitor has a very selective effect." The promising properties of the new inhibitors saw them registered in the Structural Genomics Consortium's Chemical Probe program. The Structural Genomics Consortium is a global network of research universities and pharmaceutical companies which focuses on research into genetically-determined disorders and communicates findings to researchers around the world. An important contribution has been made to it by Professor Stefan Knapp of the University of Frankfurt am Main. The Consortium also has long had ties with the University of North Carolina in Chapel Hill, one of Tübingen's partner universities in the US. "Making our inhibitors available could take basic research and the understanding of JAK signal pathways and their role in guiding the immune system a big step further in the future," Laufer says.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-1.1-3 | Award Amount: 14.62M | Year: 2010

The Affinomics programme aims to leverage existing efforts in Europe to generate large-scale resources of validated protein-binding molecules (binders) as affinity reagents for characterisation of the human proteome and to apply them in comprehensive structural and functional analyses of protein expression, interactions and complexes. Proteome targets will be focused on five categories of inter-related human proteins involved in signal transduction, cell regulation and cancer, namely protein kinases, SH2 domain-containing proteins, protein tyrosine phosphatases, proteins somatically mutated in cancers and candidate cancer biomarkers. Binders to about 1000 protein targets will be made over the course of the programme. A high throughput, coordinated production pipeline for antigens and binders will be established. Target antigens will be expressed in three forms, as folded full-length proteins or domains, as large peptide fragments (PrESTs) based on low homology to other human proteins and as small peptides, in some cases phosphorylated. Binder types to be generated include affinity-purified polyclonal antibodies, monoclonal antibodies, recombinant antibody fragments and non-immunoglobulin scaffolds. An important aspect will be the development of highly efficient next generation recombinant selection methods, based on phage, cell and ribosome display, capable of producing high quality binders at greater throughput and lower cost than hitherto. Systems and procedures for thorough binder validation and quality control will be established. The affinity reagents will be applied in advanced innovative and sensitive technologies for specific detection of target proteins and interacting protein complexes in cells, tissues and fluids, for improved understanding of protein function and new classes of diagnostic assays.

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