Abstract
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. We propose a new research line that deals with epigenetic mechanisms on a molecular level using our combined expertises 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 methyllysine binding proteins, so called histone code readers. Structural analysis provides the basis for identification and optimization of new chemical ligands for these proteins in a rational, bio-guided 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 drug targets.
Another aim is to further strengthen the network of the Freiburg community interested in Chemical Epigenetics with international key-players in this field. Thus, both scientifically and structurally we will further foster the status of Freiburg as a major site for epigenetic research.
Scientific Background
Epigenetics is defined as inheritable traits that are maintained by mechanisms other than encoding in the DNA sequence. Epigenetic mechanisms are DNA methylation and oxidation of methylcytosine within DNA, 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 are involved in the pathogenesis of many diseases and, despite their potential stability, are in principle reversible and hence also the target of epigenetic drugs. Four 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 of increasing interest with the first inhibitors of acetyl lysine binding proteins already entering clinical studies. Much less is known on inhibitors of methyllysine binding proteins. The development of new chemical tools to dissect the role of these proteins in the pathogenesis of disease is the major scientific goal of this Research Focus. Using structure based approaches combining structural biology, bioinformatics, organic synthesis and medicinal chemistry we aim to discover new small molecule ligands for acetyl- and methyl-lysine binding proteins, that will be very valuable to investigate their role in the pathogenesis of disease.
