Arbeitsgebiete / Forschung

Biological Applications

The focus of our research is a medicinal chemistry platform consisting of design, organic synthesis, and biological evaluation to develop cell permeable small molecule protein kinase inhibitors for neurodegenerative- and cancer therapy, -diagnosis and signal transduction analysis.

Concept of inhibitor design is e.g. based on scaffolds from natural compounds which are used for creating novel lead structures (e.g. from marine indole alkaloids towards pyridine-2-ones, quinolinones, and pyrazinones) for the development of selective protein kinase inhibitors. Targeted enzymes of significant interest are protein kinases such as CK-1 involved in neurodegenerative diseases (e.g. Alzheimer, neuronal inflammation), and tyrosine kinase receptors such as VEGF-R, EGF-R, FGF-R, and PDGF-R and their key downstream signalling components (PDK1). On one hand, we aim to optimize the potency and selectivity of inhibitors for a particular kinase in iterative processes. On the other hand, in light of the clinically more effective multi-kinase inhibitors we will be developing compounds with the specificity patterns for a group of therapeutically relevant (tyrosine) kinases. Optimized compounds will also be useful as radiopharmaceuticals as 18F or 124I radioactive or fluorophor-labelled compounds for in vivo visualization and detection of their biological targets.

These projects will entail in silico and structure based design of potential kinase inhibitors, the development of tractable synthetic routes to these compounds and their flexible synthesis to produce informative sets. Results from screening these compounds against the isolated enzyme as well as in a panel of kinases will be used to explore interaction of compounds with kinases and factors influencing selectivity and potency.

Rational structure based design, straight forward flexible organic chemistry/analytics, and in vitro characterization of structure activity relationships allow an effective optimization and development of potent and selective protein kinase inhibitors.

Equipment and Methods

  • Modern organic chemical synthesis lab including core routine analytical methodology (NMR, MS, LC, IR)
  • in vitro protein kinase assays for compound activity screening and evaluation of structure activity relationships
  • in vitro cellular assays and Western Blot analysis to investigate bioactivity of inhibitors and impact on cellular downstream signalling
  • Drug Design and Molecular Modelling (Schrödinger software)