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Biologically Active Organic Compounds Interacting with Adenine-binding Proteins

Final Report Summary - BIOACTIVECPDS (Biologically Active Organic Compounds Interacting with Adenine-binding Proteins)

The project's main objective has been to establish an independent productive research group by Dr. Kamil Paruch at the Department of Chemistry of Masaryk University, Brno, Czech Republic. Dr. Paruch was expected to utilize his expertise and create an interdisciplinary team which would be able to produce biologically active compounds and interact regularly with cooperating biologists.
Specifically, we have explored several central pharmacophores that were envisioned to be suitable replacements of the pyrazolo[1,5-a]pyrimidine motif we used previously in potent and selective inhibitors of selected protein kinases (e.g. dinaciclib, currently in Phase III, and SCH900776, currently in Phase II). Some direct analogs possessing certain central pharmacophores (e.g. 1,2,4-triazolo[4,3-b]pyridazine) proved to be inactive. However, within our series of substituted furo[3,2-b]pyridines we identified some inhibitors we further elaborated.
As described above, we identified new inhibitors with the furo[3,2-b]pyridine core. Subsequently, we developed methodology to elaborate the 3, 5, 6 and 7 position of the central pharmacophore and we discovered a new annulation for the construction of the furo[3,2-b]pyridine scaffold. This enabled us to identify potent (IC50 < 50 nM) inhibitors of CLK and HIPK kinases, which are emerging targets in the areas of oncology and neurodegenerative diseases. In collaboration with the Center for Technology Transfer of Masaryk University, we filed one Czech (PV 2014-295) and one international (PCT/CZ2015/000038) patent application that cover this class of compounds. These are the very first patents of Masaryk University in this area - i.e. covering new, proprietary compounds with targeted biological activity. In addition, we have developed a new flexible methodology for preparation of carbocyclic C-nucleoside analogs, which are very rare. Among several tens of these analogs, some showed interesting biological activity (e.g. inhibition of certain DNA glycosylases and cytotoxicity against cancer cells). Note: the structures of all prepared compounds are attached as a separate file.
Dr. Paruch was able to establish and develop fruitful collaboration with research (biology) groups based not only in the Czech Republic (e.g. Dr. Lumír Krejčí, Faculty of Medicine, Masaryk University; Prof. Jiří Damborský, Faculty of Science, Masaryk University; Dr. Karel Souček, Institute of Biophysics, Brno; Dr. Vladimír Kryštof, Palacky University, Olomouc), but also abroad (e.g. Dr. Yoshiyuki Mizushina, Kobe-Gakuin University, Japan; Prof. Magnar Bjoras, University of Oslo; Prof. Herbert Waldmann, Max Planck Institute, Dortmund, Germany). Some of these collaborations already resulted in joint publications.
Overall, by the end of the grant’s period, Dr. Paruch has established a productive research group that is able to carry out design and synthesis of novel biologically active organic compounds (http://orgsyn.sci.muni.cz/).