title: Selective targeting of epigenetic reader domains.
abstract: Epigenetic regulators including writers, erasers, and readers of chromatin marks have been implicated in numerous diseases and are therefore subject of intense academic and pharmaceutical research. While several small-molecule inhibitors targeting writers or erasers are either approved drugs or are currently being evaluated in clinical trials, the targeting of epigenetic readers has lagged behind. Proof-of-principle that epigenetic readers are also relevant drug targets was provided by landmark discoveries of selective inhibitors targeting the BET family of acetyl-lysine readers. More recently, high affinity chemical probes for non-BET acetyl- and methyl-lysine reader domains have also been developed. Areas covered: This article covers recent advances with the identification and validation of inhibitors and chemical probes targeting epigenetic reader domains. Issues related to epigenetic reader druggability, quality requirements for chemical probes, interpretation of cellular action, unexpected cross-talk, and future challenges are also discussed. Expert opinion: Chemical probes provide a powerful means to unravel biological functions of epigenetic readers and evaluate their potential as drug targets. To yield meaningful results, potency, selectivity, and cellular target engagement of chemical probes need to be stringently validated. Future chemical probes will probably need to fulfil additional criteria such as strict target specificity or the targeting of readers within protein complexes.
authors.affiliation: a Urologische Klinik und Zentrale Klinische Forschung , Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg , Freiburg , Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Greschik
authors.affiliation: a Urologische Klinik und Zentrale Klinische Forschung , Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg , Freiburg , Germany.|b Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg , Freiburg , Germany.|c BIOSS Centre of Biological Signalling Studies , Albert-Ludwigs-University Freiburg , Freiburg , Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: a Urologische Klinik und Zentrale Klinische Forschung , Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg , Freiburg , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
mesh_terms: D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000235:genetics; D015195:Drug Design; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005786:Gene Expression Regulation; D006801:Humans; D008239:Lysine / Q000378:metabolism; D058990:Molecular Targeted Therapy
chemical_list: D002843:Chromatin; D008239:Lysine
keywords: Acetyl-lysine reader; chemical probe; druggability; epigenetic reader; methyl-lysine reader; selectivity