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Forschungsinteressen

 research-interest-hansen

The Hansen group mainly works in the field of epigenetic drug discovery. In addition to classic organic synthesis, we are currently using various modern synthetic methods such as solid-phase synthesis, microwave synthesis and multicomponent reactions. Subsequent to the synthesis, we screen the activity of the synthesized compounds in target-based biochemical assays. This allows for a fast feedback on structure-activity relationships during the optimization cycles.

Our general research focus lies on the development of new tool compounds that are capable of reverting chemoresistance in cancer. To this end, promising compounds are assessed in different in vitro tumor models (e. g. antiproliferative effects, induction of apoptosis, and effects on cell cycle). Additional in-depth evaluation of biological and structural properties (including synergism experiment, in vivo studies, and X-ray crystallography) takes place in collaborating research groups across the globe.

Over the last years, our group has gained broad experience in developing histone deacetylase (HDAC) inhibitors. As important modifiers of the histone structure and non-histone proteins, HDACs regulate gene expression and other pathways with effects on cellular events including the cell cycle, angiogenesis, cytoskeleton formation, protein degradation, and resistance to chemotherapy. Overexpressed in several tumor types, HDACs have been identified as valuable drug targets for targeted cancer therapy.

Besides their potential as targets for single-agent drugs, HDACs are also known to participate in synergistic pathways with several other drug targets, including BET proteins, the 26S proteasome, and Hsp90. This implicates the excellent suitability of HDAC inhibitors for combination therapies but collides with the complications of polypharmacy. To overcome these drawbacks, we utilize the advantages of polypharmacology and aim at designing dual-targeting inhibitors that are capable of inhibiting two synergistic drug targets.

Beyond the field of cancer, our research on small-molecule HDAC inhibitors also specializes in the development of antimalarial agents. In this regard, we are particularly interested in identifying compounds with activity against multiple malaria parasite life cycle stages that might ultimately provide drug candidates with causal prophylactic and/or transmission blocking properties.

In another research area, we are interested in proteolysis-targeting chimeras (PROTACs) as a new class of chimeric small molecules. PROTACs are bifunctional modalities that are able to hijack the cellular protein degradation system by recruiting the protein of interest (POI) to E3 ubiquitin ligases, thus leading to polyubiquitinylation of the POI and induction of its proteasomal degradation. However, the synthesis of PROTACs is usually cumbersome and involves multi-step protocols due to the high molecular weight and bifunctional nature of the compounds. Hence, we are currently developing efficient solid-phase supported protocols for the synthesis of protein degrader libraries.

 

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