Potent and selective protein kinase inhibitors from the sea

Due to lifestyle changes and an increasing percentage of elderly citizens, the incidence of cancer is increasing, and the pharmaceutical industry has struggled in providing new and efficient cancer treatments. Kinases are enzymes that have essential roles in regulation of signaling pathways that control normal cell functions. The over-activation of protein kinases is associated with a wide range of pathologies such as cancer, infectious and inflammatory diseases, diabetes and cardiovascular disorders. Inhibitors of protein kinases include small organic molecules with a pharmacokinetic profile that allows for oral administration. Such inhibitors can rapidly alter the activation state of a target kinase, thus making protein kinases attractive targets for the development of drugs for the treatment of cancer. Administration of conventional cytotoxic drugs is often associated with severe side effects, while inhibition of kinase activity can often be tolerated by normal cells. This gives us an opportunity for selective killing of tumor cells. MabCent, a center for research-based innovation (CRI) of marine bioactives and drug discovery hosted by UiT The Arctic University of Tromsø, has since 2007 screened extracts from a wide array of marine organisms for compounds with biological activity, including inhibition of protein kinases. During this screening campaign we have identified several molecules with promising kinase inhibitory properties. In the KINSEA project we wanted to create a compound library inspired by the molecules we have isolated from the marine organisms, and to optimize their activity against selected pharmaceutically relevant kinases. The main goal of the project was to nominate a lead candidate that could be developed into a commercial drug for the treatment of cancer. We have synthesized the natural occurring compounds and confirmed their activity against relevant kinases. Based on the activities of the natural occurring compounds, we have nominated the target kinases for the project. We have synthesised four "generations" of compounds based on the structure-activity-relationship (SAR) indicated by the original compounds. As part of these studies we have established assays for the relevant kinases at Marbio in order to rapidly test the activity of the synthesized compounds. The most potent inhibitors have been profiled for their selectivity and potency against a broad panel of kinases, and their ADMET properties have been studied. We have managed to obtain a 10-fold increase in potency for our most active inhibitors.

MabCent, a center for research-based innovation (CRI) of marine bioactives and drug discovery hosted by UiT The Arctic University of Norway, has since 2007 included protein kinase inhibition assays in its screening campaign of marine extracts. Through the MabCent screening we have identified several marine natural products that inhibit the activity of kinases relevant for treatment of cancer. We have now identified a family of novel compounds with IC50-values in the nM range against a set of kinases that we want to pursue. Based on the data we have generated so far we are seeking funding for a project aimed at advancing these novel kinase inhibitors further through the biodiscovery pipeline with the ultimate goal to identify lead compounds for further drug development. This will be achieved through three work packages: 1) Assessment of biological activity through in vitro and in vivo models. 2) Optimization of biological activity through chemical synthesis. 3) Early toxicity profiling through in vitro and in vivo models.