Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany./ University of Oxford, Nuffield Department of Clinical Medicine, Oxford
Bromodomains (BRDs) are evolutionary conserved protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The human proteome encodes 61 of these highly diverse domains present in 46 mainly nuclear proteins. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. During the recent years we have established a family wide platform of reagents, assays and crystal structures enabling the rational design and comprehensive selectivity screening of bromodomain inhibitors. Using this platform we and our collaborators have developed and comprehensively characterized highly selective chemical tool compounds (chemical probes) for most bromodomain subfamilies. In this talk I will present recent data on the developed tool compounds that cover now most bromodomain subfamilies including their in vitro characterization and phenotypic responses observed in cellular model systems as well as their potential for the development of new targeted therapies. I will also show examples how the unencumbered availability of chemical probes leads to rapid validation of new therapeutic strategies in diverse disease areas. Recent development of bromodomain targeting PROTACs (proteolysis targeting chimera) will also be discussed.