Working Group Hansen

Over the past years, our group has gained broad experience in the development of histone deacetylase (HDAC) inhibitors. HDACs are crucial modifiers of histone structure and non-histone proteins, governing gene expression and various cellular pathways such as the cell cycle, angiogenesis, cytoskeleton formation, protein degradation, and chemotherapy resistance. Given their overexpression in multiple tumor types, HDACs represent valuable targets for targeted cancer therapy. Furthermore, our lab also explores other epigenetic drug targets, including bromodomains and histone acetyltransferases.

In addition to being potential targets for single-agent drugs, HDACs also play a role in synergistic pathways alongside other drug targets such as 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 multi-target drugs that are capable of inhibiting relevant HDAC isoforms as well as other synergistic drug targets.

Protein-protein interactions (PPIs) often involve large and shallow binding sites with extensive surface areas, making it difficult to design small molecules that can effectively bind and inhibit PPIs. To overcome this, we employ α-aminoxy peptides as α-helix mimetics that replicate hot spot amino acids in α-helices. Through this approach, we successfully developed aminoxyrone (AX), a novel peptidomimetic C-terminal HSP90 inhibitor. Our strategy targets HSP90 dimerization via the C-terminal domain (CTD), resulting in the destabilization of BCR-ABL1 without inducing the resistance mechanism of a heat shock response (HSR) both in vitro and in vivo.

In this research area, we focus on proteolysis-targeting chimeras (PROTACs), a new class of targeted protein degraders. These bifunctional compounds exploit the cellular protein degradation system by recruiting the protein of interest (POI) to E3 ubiquitin ligases. This leads to the polyubiquitinylation of the POI and its subsequent proteasomal degradation. However, synthesizing PROTACs is often complex due to their high molecular weight and bifunctional nature. To overcome this, we utilize an efficient solid-phase supported protocol for protein degrader library synthesis.