Jump label

Service navigation

Main navigation

You are here:

Main content

Research

The completion of the Human Genome Project has sparked a new era in genome analysis and immediately raised the fundamental question of how to translate the wealth of genetic information into the development of innovative new medicines. Over the last decade, it became evident that nucleotide sequence-based approaches alone cannot bridge the genotype-phenotype gap since individual gene products are not self-contained functional entities in cells. The key is to understand the dynamics of gene product function in complex systems. To follow this notion, we use organic synthesis and chemical genetic strategies to selectively target proteins of interest (Fig. 1). Structural biology assists us in the design and development of inhibitors and site specific molecular probes for perturbation experiments in cellular systems. In particular, we are interested in aberrantly regulated processes that can lead to abnormal cell behavior such as neurodegenerative diseases, cancer and pathogen invasion. We hope that our techniques and investigations will not only lead to a better understanding of protein function in complex systems, but also stimulate the development of new drugs.

 

fig1_600

Figure 1 Interdisciplinary setup of the group.
(a) We are stimulated by pharmacological or biological questions. Structural biology assists our organic synthesis initiatives to create new inhibitors and functional probes which are then used in biological systems to dissect protein function.
(b) How do proteins function? A library of small molecules is screened using cell assays to identify one with interesting biological activity. Pull-down experiments and mass spectrometry analysis help to identify target proteins associated with the observed phenotypes. Structural biology and the understanding of protein ligand interactions assist in the design of molecular probes – such as fluorescent reporters – to dissect protein function at the cellular level.

 

 

Research areas:

Allosteric kinase inhibitors

Compounds binding to less conserved sites outside the highly conserved ATP pocket of kinases, are thought to have superior selectivity profiles and offer new opportunities for scaffold development. We develop innovative assay systems that allow for the detection of allosteric kinase inhibitors in high-throughput. We use structure based design and organic synthesis approaches for the development of inhibitors and functional probes to target inactive kinase conformations.

 

res01_400

 

Dissection of oncogene dependencies by small organic molecule perturbations

Here we seek to define new drug-lesion pairs that are therapeutically attractive to targeted cancer therapy. We design and synthesize small organic molecules to probe functions of mutated oncogenes in both cellular and in vitro systems. Fluorescent functional probes are used to investigate the spatial and temporal distribution of mutated human oncogenes in living cells. Cellular studies assist us in the identification of determinants of response in order to define new principles of pharmacological vulnerability.

 

res02_400

 

Drug resistance in targeted cancer therapy

Resistance mutations are emerging at an increasingly rapid pace and often limit the success of newly available targeted cancer therapies. We aim to understand the molecular basis of such mutations and seek to develop new chemical principles to overcome drug resistance. Here we use structural biology to understand drug resistance mutations in oncogenes followed by structure based drug design to develop small organic molecules that overcome mutation-related drug resistance.

 

Collaborators:

Priv.-Doz. Dr. Roman Thomas, Max Planck Institute for Neurological Research, Cologne, Germany

 

 

Design, synthesis and application of functional probes

We use fluorophore equipped inhibitors as functional probes for targeting proteins of interest. Life cell imaging experiments allow us to dissect protein network dynamics in cellular processes.

 

res04

 

Collaborators:

Dr. Silke Hauf, Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Prof. Dr. Philippe Bastiaens & Dr. Hernan Grecco, Max Planck Institute of Molecular Physiology, Dortmund, Germany

 

 

De novo structure determination

We focus on the elucidation of novel target protein structures from various organisms by protein X-ray crystallography. The detailed understanding of the three dimensional architecture of a given target protein enables rational design of chemical entities which allow for either inhibition or modulation of the biological functions of these targets

 

res05_400

 

Collaborators:

Dr. Guido Sessa, Tel Aviv University, Israel

 

 

Targeting parasites & target identification

Parasites and infectious diseases are a rapidly growing, yet underestimated threat. Kinase inhibitors are not only of great interest in the field of cancer research, they might also offer a great potential in targeting parasites and infections. So while classical medicinal research focuses on reversing kinase malfunction, here we aim at evoking kinase malfunction to inhibit parasite or pathogen growth. In addition, we are interested in the identification of potential target proteins. We apply pull-down experiments and mass spectrometry analysis for target identification and chemical genetic strategies for chemical target validation.

 

res06_400

 

 

We are grateful to funds from:

NGFNplus program of the BMBF

Alexander von Humboldt Foundation

Companies

 

 



Sub content

  

180611_Logo_DDHD_CMYK

  

Ziel2NRW_RGB_1809_jpg

  

EFRE_Foerderhinweis_deutsch_farbig

Learn more about the EMODI Project

  

885px-Landesregierung_Nordrhein-Westfalen_Logo.svg

  

231px-BMBF_Logo.svg

logo

  

DFG-logo-final