Journal Article

Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes

Grandi, Paola, Strunk, Katja, Ramsden, Nigel G, Drewes, Gerard, Eberhard, Dirk, Neubauer, Gitte, Boesche, Markus, Reader, Valérie, Michon, Anne-Marie, Huthmacher, Carola, Sweetman, Gavain, Bantscheff, Marcus, Schlegl, Judith, Hopf, Carsten, Mathieson, Toby, Bergamini, Giovanna, Poeckel, Daniel, Becher, Isabelle, Kruse, Ulrich, Abraham, Yann, Dittmann, Antje, Delling, Manja, Savitski, Mikhail M, Dümpelfeld, Birgit

2011

Overview

Bantscheff et al . use chemoproteomics to measure the affinity of small molecules for megadalton protein complexes in cell extracts. Differences in the selectivity of HDAC inhibitors observed when native HDAC complexes are compared with their purified catalytic subunits suggest the limitations of using isolated recombinant proteins in certain drug screens. The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/154/555 / 631/61/475 / Agriculture / Anti-inflammatory agents / Antimitotic agents / Antineoplastic agents / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Enzyme inhibitors / Enzymes / Fundamental and applied biological sciences. Psychology / Health aspects / Health. Pharmaceutical industry / Histone Deacetylases - chemistry / Histone Deacetylases - metabolism / Hydrolases / Industrial applications and implications. Economical aspects / Inhibitors / Life Sciences / Mass spectrometry / Mass Spectrometry - methods / Miscellaneous / Peptide Mapping - methods / Phylogenetics / Physiological aspects / Protein folding / Protein Interaction Mapping - methods / Proteomics / Proteomics - methods