Abstract

Selective Targeting Of Epigenetic Reader Domains

Stefan Knapp, Professor, Goethe Institut Franfurt

The epigenetic code is interpreted by a large diversity of epigenetic reader domains which have key functions in regulating tissue specific transcription and in bookmarking of actively transcribed genes during cell division. Our laboratory is interested in understanding the molecular recognition processes mediated by reader domains and in the development of protein interaction inhibitors that specifically target these protein families. Our main interest is focussed on readers recognizing e-N-lysine acetylation motifs, epigenetic marks that are principally read by bromodomains (BRDs). 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 highly selective chemical tool compounds 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.