The research in our laboratory focuses on the development of synthetic methods and strategies for preparation of structurally non-trivial small molecules for applications in biomedical research. Our lab is part of an interdisciplinary research platform - Center of Biomolecular and Cellular Engineering - within the International Clinical Research Centre of St. Anne´s University Hospital in Brno and Mayo Clinic in Rochester, Minnesota (USA). Research funding is provided through national and international resources: FP7, EU-Structural Funds, Grant Agency of the Czech Republic, Grant Agency for Health Research of the Czech Republic, Alfred Bader (private support) and Masaryk University.
Chemistry and biology of forskolin
Structurally complex diterpene forskolin is a known allosteric activator of adenylyl cyclases, key enzymes involved in the production of second messenger cAMP. Semisynthetic analogs of forskolin provided an important proof-of-principle in therapeutic targeting of adenylyl cyclases (colforsin is a drug approved in Japan). The pharmacology of adenylyl cyclases is complex however and much remains to be learned.
Our laboratory is re-examining the potential of forskolin. Towards this end, we recently reported the shortest synthetic route to this complex target (24 steps). These developments enabled us to produce hundred-milligram quantities of forskolin and more importantly, opened path to fully synthetic analogs modified at positions inaccessible by semisynthesis. By profiling the new forskolin analogs in a panel of all isoforms of human adenylyl cyclases (in collaboration), we hope to identify molecules with improved potency and/or isoform selectivity.
Selective kinase inhibitors
Protein kinases regulate a wide range of cellular functions including initiation of cancer cells, tumor progression, and the development of metastatic diseases. Many of them therefore represent attractive targets for modern oncology. Up to date, more than thirty kinase inhibitors have been approved for clinical use.
Part of our research is focused on identification and development of new (patentable) potent and highly selective inhibitors of selected „non-routine“ kinases, especially CLKs, HIPKs and CK1delta/epsilon. The ultimate ambition of these projects, which are run in close collaboration with top-class biologists, is identification of state-of-the-art chemical biology probes that would be suitable for further preclinical progression. In addition, we develop new inhibitors of CHK1 kinase, utilizing the concept of synthetic lethality.
Inhibitors of DNA repair pathways
DNA nucleases are key enzymes responsible for processing strands of DNA following damage. Present in all cell types, nucleases are one of the first enzyme mediators recruited to the site of DNA damage in cells and play crucial roles in various DNA repair pathways ensuring stability of the genome.
While nucleases have been relatively underexplored in terms of their pharmacological inhibition, we believe that nuclease inhibitors could have broad potential as selective treatments for a range of cancers, particularly in tumours that have defects in their DNA repair processes and are reliant on alternative DDR pathways which are mediated by nucleases. The opportunity may also exist to use nuclease inhibitors in combination with other cancer therapies, including standard of care treatments such as ionizing radiation, and potentially together with emerging therapies such as immuno-oncology treatments.
The project focused on the development of novel cancer treatments targeting DNA nucleases is done in collaboration with the innovative Cambridge-based company Artios Pharma (for more, see the section News).