Bifunctional chemical tools to probe reversible lysine acetylation and methylation

Reversible posttranslational modification of the side chains of lysine in histones and other proteins is an important cellular regulation mechanism in epigenetics, membrane anchoring and signalling. Among these acetylation and methylation are the most prominent, have led to the validation of drug targets and the approval of drugs against deacetylases and methyltransferases for the treatment of cancer and clinical trials for other diseases are underway. We have worked on target validation, assay development, screening and structure based inhibitor optimization on various targets in the space of lysine acetylation and methylation. Here we present bifunctional tools such as PROTACs ( Proteolysis targeting chimeras), biotinylated and fluorescent compounds to dissect lysine modification pathways and as potential drugs. Exemplary studies deal with the lysine deacylase Sirt2, the methyl lysine binding domain of the chromatin remodeller CHD1 and the lysine methyltransferase KMT9.