Research

We investigate modes of action of investigational drugs by identifying drug targets, characterizing global perturbations and biomarker signatures, as well as delineating the expected clinical benefit. Particularly, we establish and apply analytical methods to comprehensively elucidate cellular processes. The sources of biological samples are versatile and include cells, subcellular fractions, tissues, blood and sweat.

Target identification. We employ chemoproteomic approaches to generate hypotheses about potential protein targets. Custom probes are specifically prepared for this purpose. This is a powerful strategy for target prioritization in the biological complexity, enabling a detailed description of the target landscape. We typically perform differential chemoproteomics to account for unspecific binding and probe interaction strength by dose-dependent target profiling experiments.

References:

Neuditschko et al., Angew. Chem., Int. Ed., 2022
Skos et al., Curr. Opin. Chem. Biol, 2023

Perturbation profiles. Mass spectrometry-based omics techniques aid in characterizing drug-induced perturbations because of their hypothesis-generating power. Perturbation studies are enabled by the identification of molecular events that are mapped to biological processes and the resulting perturbation networks aid in elucidating drug modes of action. Importantly, the quality of the perturbation profile is influenced by experimental and statistical workflows, which determine the number of significant and explainable molecular alterations. Rigorous bioanalytical methods are designed and employed to control the precision of experiments and maximize the information content of perturbation studies.

Reference:    Bortel et al., PNAS, 2024

Degradome analysis. Proteolysis targeting chimeras (PROTACs) are bifunctional molecules designed to induce the degradation of specific proteins within a cell. We established a cycloheximide chase assay in a non-proliferative steady-state cell culture model. This approach enables the identification of PROTAC degradation targets uncoupled from confounding effects originating from cell-cycle-dependent translational patterns.

Reference:     Thomas and Iellici et al., ACS Chem. Biol., 2026.
 

Despite the success of metal-based anticancer agents in the clinics, inorganic drug discovery programs remain purely academic to date. This can be partially explained by the perceived risks of unspecific effects and toxicity of these reactive molecules. Indeed, metal-based compounds can undergo ligand exchange, redox reactions and bind to targets via the metal centre. This is a unique feature of this compounds class, as coordinative bonds differ fundamentally from covalent bonds. On the one hand, this reactivity enables their beneficial therapeutic effects, but on the other hand, it is difficult to control. Our efforts in target identification and mode of action discovery have shown that, contrary to the still widespread believe, metal-based candidate drugs can be highly specific agents. To identify probable interactors, targets from chemoproteomics are combined with perturbation signatures of the same compound in cells because a true drug target must be causally linked to its cellular effects. The resulting target-response networks and dose-dependent target profiling have proven highly effective in prioritizing drug targets for metal-based compounds. We were able to show that the reactivity of metal-based candidate drugs can be exploited to engage hard-to-drug targets and unusual modes of action.

References:

Rosner and Skos et al., Chem. Sci., 2025.

Skos and Schmidt et al., Cell Rep. Phys. Sci., 2024.

Neuditschko et al., Angew. Chem., Int. Ed., 2021.

Plecstatin-1. We discovered plecstatin-1 (PST), a covalent organoruthenium lead structure, and first-in-class plectin inhibitor. This compound was shown to be highly selective for plectin on a proteome-wide scale. Plectin targeting by PST mirrored plectin knock-out phenotypes resulting in reduced intercellular cohesion. Moreover, PST inhibited hepatocellular tumour growth in mouse models and led to a pronounced reduction of micrometastases in the lungs of treated animals. PST can be orally administered, and the treatment is well tolerated by the animals over extended time periods. PST was also found to induce reactive oxygen species and an integrated stress response in mitochondria upon phosphorylation of eIF2α.

References:    

Outla et al., eLife, 2025.

Meier et al., Angew. Chem., Int. Ed., 2017.