Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - TAROX (Targeting oxidative repair proteins for treatment of cancer and inflammation)
Teaser
A fundamental problem in today’s healthcare is that we have insufficient treatment options to highly prevalent diseases, including cancer and inflammatory disorders. The disease-causing cells often have unbalanced redox homeostasis and deregulated reactive oxygen species...
Summary
A fundamental problem in today’s healthcare is that we have insufficient treatment options to highly prevalent diseases, including cancer and inflammatory disorders. The disease-causing cells often have unbalanced redox homeostasis and deregulated reactive oxygen species (ROS). We have insufficient knowledge today into which proteins are involved in preventing or repairing oxidative DNA damage. Surprisingly, targeting proteins involved in managing oxidative DNA damage is pharmaceutically unexplored, while this could offer great potential to make a real difference in many common diseases.
A big challenge the society is facing, is that today’s health care are focused more on reducing symptoms rather than attacking the underlying cause of the disease. With the granted money, we are addressing this challenge by targeting the repair processes of oxidative DNA damage, known to be affected in cancer and inflammatory disorders, this in order to develop novel therapeutics that has a potential to treat the underlying cause of the disease. The outcome of this programme, if successful would be new therapeutic interventions for many forms of cancer, many different autoimmune, neurological and viral diseases.
The overreaching objective for this on-going project is to increase the understanding of how repair of oxidative DNA damage is involved in disease etiology. Furthermore, to introduce a completely novel therapeutic approach to cancer, inflammation, neurodegenerative and viral diseases, based on first-in-class inhibitors to proteins involved in repair of oxidative DNA lesions. To achieve this, we are taking an interdisciplinary approach to i) develop tools, probes, to study proteins involved in metabolism and repair of oxidative DNA lesions, ii) understand the biological role of oxidative repair proteins and relevance in disease and iii) identify and explore inhibitors (e.g., to MTH1 and OGG1) in cancer, inflammation, neurodegenerative and viral diseases.
Work performed
Up to date, we have in the research group the total purified compounds/targets as following: 18 nudix proteins, 8 glycosylases and 3 small GTPases, proteins involved in nucleotide metabolism and oxidative repair mechanisms. Producing these proteins help to reveal the biology and biochemistry behind the repair of oxidative DNA damage, and is a base for identifying chemical probes (inhibitors). The availability of chemical probes is absolutely central for making advances in this field. When we started this project, small molecule inhibitors selectively targeting oxidative repair pathways was largely missing. We have made e.g. MTH1, NUDT5, NUDT15, and OGG1 inhibitors and published the findings in international recognised scientific journals (e.g., Nature and Science) and made them available to the scientific community. In our lab, we have made an orally available and well-tolerated MTH1 inhibitor, which is effective in most cancer disease models, also including multi-drug resistant ones. The most advanced compounds is now tested in advanced cancer patients with solid malignancies.
Final results
We have focused our attention on studying a completely neglected family of enzymes, the Nudix hydrolases, and also glycosylases, which has not received huge attention. The rationale being that oxidative metabolism and repair is highly relevant to biology and disease. We have already taken one of our ideas, targeting MTH1 (NUDT1) from idea into clinical phase 1 trial during the progress of this programme.
We will contribute with novel tool compounds to be used in further understanding of oxidative repair pathways. We will, if successful, identify novel targets and develop selective and potent drugs for treating cancer, inflammation based autoimmunity and/or virus infections.