A NEW DRUG FOR TREATING AUTOIMMUNITY BY BLOCKING LYMPHOCYTE ENERGY GENERATION

The goal of this Rheumatech AS project is to develop a drug for the treatment of autoimmune disease. The drug will inhibit crucial white blood cell mechanisms that cause harmful immune activity. The project was initiated June 2012. Since then we have optimized several compounds that are actively inhibiting the effect of our target protein. Preliminary data concerning toxicity has been collected and assessed. Compound metabolism and pharmacokinetics data are being collected in parallel with medicinal synthesis of compounds to direct further synthesis. The biological cell-based proliferation assay method, the mass spectrometry based activity analysis and a new method to analyse compound-protein interaction based on thermophoresis have all been established and utilized to collect data describing the efficiency of the analysed compounds. A new screen of three chemical libraries has also been conducted to expand the pool of hit compounds for refinement. Hits from this screen have been purchased to verify activity and serve as starting points for further synthesis and optimization. Subsequent compound purchases have been made with the most biochemically and biophysically promising hit serving as starting points. The murine autoimmune animal model has been established and example compounds have been tested. Crystallization studies examining the interaction between protein and compounds have been carried out. The compounds? inhibitory activity has been measured and subsequently analysed utilizing our well established and effective bioinformatical tools. Interesting verified hits have been selected for more thorough characterization and form the basis for collecting and synthesizing groups/series of similar compounds with inhibitory effect. This collection has been carried out in two stages to increase our understanding of the correlation between structure and effect. Series of interesting compounds have been further analysed to assess their solubility in water, ability to be taken up by cells and how they are treated by the systems in the body breaking down foreign compounds. Different biophysical studies on how the compounds interact with our target protein have been carried out and have yielded positive results. Further synthesis of compounds analogous to our best performing compounds has been prepared by our collaboration partners in Oslo.

Rheumatech's innovation is a drug with a novel target that can be used to treat and improve life quality of patients suffering from autoimmunity. The R&D project entails the development of a drug candidate that will have initiated pre-clinical analyses in the process of approval for Phase 1 clinical trials.The drug will be a highly desirable alternative to current therapeutic regimes and provide Rheumatech with a huge market potential and generate significant value. Autoimmunity constitutes many differen t diseases including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes which are all life-lasting, associated with severely reduced life quality and may in some cases be life-threatening. Autoimmunity is with cancer and cardiovascula r disease ranked as the most common causes of morbidity in the world today. All forms of autoimmunity are associated with an over-active immune system and multiplying self-destructive white blood cells degrading and damaging the body's own tissue. Rheum atech has successfully identified chemical compounds (verified hits) that block the target protein and thereby block energy generation in proliferating white blood cells. Rheumatech's R&D challenges in the proposed project are achieving sufficient drug sp ecificity and affinity and minimizing side-effects and toxicity. We aim at achieving our objectives by using high-quality chemical structure synthesis and analysis, bioinformatics and studies in a whole-animal disease model. The development will include h it confirmation and clustering, optimization of hits for animal testing, development of a biological test model for proof of concept experiments, lead optimization and clustering and finally preparation for preclinical trails. The project is planned to be performed in collaboration with University of Oslo, Oslo University Hospital, the Norwegian Institute of Public Health and German drug discovery companies Evotec and Biaffin.