Transcriptional profiles are significantly altered in cancer resulting in increased expression levels of growth promoting genes. Many of these altered expression profiles are due to dysfunction of epigenetic processes such as changes in DNA methylation, histone acetylation and methylation levels. These alterations lead to changes is chromatin structure and aberrant binding transcription regulators that are recruited of these promoters by proteins that carry specific recognition domains for histone marks.
In my laboratory we are interested in understanding the role of bromodomain (BRD) proteins in gene transcription. Bromodomains are evolutionary conserved protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. We are approaching this problem by developing highly selective inhibitors that target these interfaces and that act as chemical probes by interfering with recruitment process of bromodomains to acetylated histones and other nuclear proteins.
The acetyl-lysine binding pocket has been identified as an attractive binding site for the development of inhibitors. Recently, a number of highly specific and potent inhibitors for BET bromodomains have been reported by us and other laboratories. For instance, we developed the pan-BET inhibitors JQ1 and PFI-1. We are now interested to develop highly specific chemical probe molecules for bromodomains outside the BET family and successfully targeted the bromodomain of the acetyl transferases CBP/EP300, and the chromatin remodelling proteins SMARCA2/4 and BAZ2B.