title: Chemoproteomics reveals time-dependent binding of histone deacetylase inhibitors to endogenous repressor complexes.
abstract: Class I histone deacetylases (HDACs) are attractive drug targets in oncology and inflammation. However, the development of selective inhibitors is complicated by the characteristic that the localization, activity, and selectivity of class I HDACs are regulated by association in megadalton repressor complexes. There is emerging evidence that isoform and protein complex selectivity can be achieved by aminobenzamide inhibitors. Here we present a chemoproteomics strategy for the determination of time-dependent inhibitor binding to endogenous HDACs and HDAC complexes. This approach enabled us to determine kinetic association and dissociation rates for endogenously expressed repressor complexes. We found that unlike hydroxamate type inhibitors, aminobenzamides exhibited slow binding kinetics dependent on association within protein complexes. These findings were in agreement with a delayed cellular response on acetylation levels of distinct histone sites and the inability of aminobenzamides to inhibit HDAC activity of a Sin3 complex isolated from K562 cells.
authors.affiliation: Cellzome GmbH, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Becher
authors.forename: Antje
authors.initials: A
authors.lastname: Dittmann
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Savitski
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
mesh_terms: D000107:Acetylation; D001549:Benzamides / Q000037:antagonists & inhibitors; D001665:Binding Sites; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D007700:Kinetics; D013058:Mass Spectrometry; D040901:Proteomics; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins