CORDIS - EU research results

Systems Chemical Biology - Chemical Biological Perturbation and Dissection of Dynamic Biological Systems

Final Report Summary - SYSCHEMBIOL (Systems Chemical Biology - Chemical Biological Perturbation and Dissection of Dynamic Biological Systems)

The chemoinformatic analysis of more than 180,000 natural product (NP) structures (Goal 1) identified 2,000 clusters of NP-derived fragments which resemble the properties of NPs themselves and populate areas of chemical space not occupied by average synthetic molecules. The use of natural product-derived fragments enabled a novel approach to the syntheses of natural product-inspired compound collections which may serve to overcome the limitations in the use of natural products in drug discovery due to lack of accessibility and synthetic tractability as demonstrated by Over et al (Goal 2). Numerous novel synthesis routes were developed to access NP-inspired small molecules that led to the preparation of focused compound collections (Goal 3). Cell-based screening identified small molecule modulators of various cellular processes e.g. mitosis, cytokinesis, Wnt and Hedgehog signaling, neurite outgrowth and glucose uptake (Goal 4). Detailed investigation of the mechanisms of action of the hit compounds revealed inhibitors of microtubule dynamics, myosin light chain kinase (MLCK), 5-lipoxygenase, Smoothened, the protein kinase MAP4K4, the calcium ion channels TRPC4/5, Casein Kinase I and other targets that are still under investigation. For some of the identified target proteins, small molecule modulators were not reported so far or display only low potency (TRPC4/5, MLCK and the glucose transporter GLUT1). Thus, the small molecules characterized in the SysChemBiol project are valuable tools for the investigation of biological processes that are regulated by or involve the respective proteins. Moreover, one class of mitotic inhibitors, the TRPC4/5 agonist Englerin A and GLUT1 inhibitors were transferred to the Lead Discovery Center (LDC) of the Max Planck Society (Goal 5) to identify lead compounds that can be further pursued by the pharmaceutical industry. Of these three projects, the studies on TRPC4/5 and GLUT1 are ongoing, whereas the mitotic inhibitors were discontinued.
Overall, thanks to the support of SysChemBiol the set goals could be reached and the achievements of this highly interdisciplinary approach, which was mandatory for this completion of, are nicely reflected in the high quality publications that resulted and will result from these studies.