Topic

Topic of the Research Focus

Epigenetics is one of the major topics of modern biomedical research and is already a major focus in the Freiburg research landscape with international visibility. The Research Focus deals with epigenetic mechanisms on a
molecular level using our combined expertise in synthetic organic and medicinal chemistry, structural biochemistry and bioinformatics to address this topic in a highly synergistic manner. The main scientific focus of our project will be acetyl and methyl lysine binding proteins, so called histone code readers. Structural analyses provide the basis for identification and optimization of new chemical ligands for these proteins in a rational, bioguided fashion. This will lead to new chemical tools that will allow dissecting cellular pathways involving these proteins as well as the analysis of their suitability as targets in drug discovery. The structural aim of this project is the preparation of a proposal for an International Research Training Group. Thus, both scientifically and structurally we will further foster the status of Freiburg as major site for epigenetic research.

Scientific Background

Epigenetics is defined as inheritable phenotypic traits that are maintained by mechanisms other than encoding in the DNA sequence. Epigenetic mechanisms are DNA methylation and oxidation of methylcytosine within DNA, small non-protein coding RNAs and a whole set of posttranslational histone modifications. Epigenetic modifications can be highly susceptible to external stimuli such as chemicals, nutrition or even stress. Yet, they may then be very stably inherited over mitotic cell division almost like a genetic mutation. These so-called epimutations have been recognized to be involved in the pathogenesis of many diseases and, as they despite their potential stability are in principle reversible, are also the target of epigenetic drugs. Six epigenetic inhibitors are already approved for the treatment of cancer. Among the histone modifications lysine methylation is an emerging target with the first inhibitors of lysine methyltransferase or demethylases in Phase I clinical trials as anticancer agents. Furthermore, proteins that recognize histone acetylation or methylation, so called histone code readers, are a very promising target class with the first inhibitors of acetyl lysine binding proteins entering clinical studies as well. Much less is known on inhibitors of methyl-lysine binding proteins and the development of new chemical tools to dissect the role of these proteins in the pathogenesis of disease is the major scientific focus of this Research Focus. Using structure based approaches combining structural biology, cheminformatics, organic synthesis and medicinal chemistry we want to discover new small molecule ligands for methyl lysine binding proteins that will be valuable to investigate the role of these proteins in the pathogenesis of disease.