Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes.
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.
Cellzome AG, Heidelberg, Germany. marcus.bantscheff@cellzome.com
Marcus
M
Bantscheff
Carsten
C
Hopf
Mikhail M
MM
Savitski
Antje
A
Dittmann
Paola
P
Grandi
Anne-Marie
AM
Michon
Judith
J
Schlegl
Yann
Y
Abraham
Isabelle
I
Becher
Giovanna
G
Bergamini
Markus
M
Boesche
Manja
M
Delling
Birgit
B
Dümpelfeld
Dirk
D
Eberhard
Carola
C
Huthmacher
Toby
T
Mathieson
Daniel
D
Poeckel
Valérie
V
Reader
Katja
K
Strunk
Gavain
G
Sweetman
Ulrich
U
Kruse
Gitte
G
Neubauer
Nigel G
NG
Ramsden
Gerard
G
Drewes
D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods*; D010449:Peptide Mapping / Q000379:methods*; D025941:Protein Interaction Mapping / Q000379:methods*; D040901:Proteomics / Q000379:methods*
D006655:Histone Deacetylases
Cell. 2007 Feb 23;128(4):693-705
17320507
Curr Opin Genet Dev. 2008 Oct;18(5):404-10
18929655
Cell. 2009 Dec 11;139(6):1029-31
20005793
Nat Rev Drug Discov. 2006 Sep;5(9):769-84
16955068
J Proteome Res. 2009 Oct;8(10):4743-52
19663507
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2431-6
20133760
J Mol Biol. 2004 Apr 16;338(1):17-31
15050820
EMBO Rep. 2008 Jun;9(6):555-62
18451879
Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1171-6
17227860
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17335-40
17956988
Cell. 2009 Sep 4;138(5):1019-31
19698979
Mol Cell Proteomics. 2008 Sep;7(9):1702-13
18511480
Nat Methods. 2009 Oct;6(10):741-4
19749761
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4617-22
19255428
J Am Soc Mass Spectrom. 2010 Oct;21(10):1668-79
20171116
J Pharm Pharmacol. 2003 Oct;55(10):1379-88
14607020
J Biol Chem. 2008 Dec 19;283(51):35402-9
18953021
Bioorg Med Chem Lett. 2008 Mar 15;18(6):1814-9
18308563
Genes Cells. 2007 Aug;12(8):941-59
17663723
Science. 1996 Apr 19;272(5260):408-11
8602529
Science. 2009 Aug 14;325(5942):834-40
19608861
Cell. 1997 May 2;89(3):357-64
9150135
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11811-6
20547842
Life Sci. 2008 May 23;82(21-22):1050-8
18455194
J Proteome Res. 2010 Nov 5;9(11):5511-6
20836569
Nat Rev Mol Cell Biol. 2008 Mar;9(3):206-18
18292778
Biochem J. 2008 Jan 15;409(2):581-9
17868033
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1454-8
11171972
Mol Cell Proteomics. 2005 Dec;4(12):2010-21
16249172
Nat Biotechnol. 2007 Jan;25(1):84-90
17211407
Nature. 2006 Mar 30;440(7084):631-6
16429126
Science. 2010 Feb 19;327(5968):1000-4
20167786
Genes Dev. 1999 Aug 1;13(15):1924-35
10444591
Oncogene. 2007 Aug 13;26(37):5468-76
17694087
J Proteome Res. 2010 Aug 6;9(8):4045-52
20515019
Nat Biotechnol. 2007 Sep;25(9):1035-44
17721511
J Biol Chem. 2001 Oct 12;276(41):38307-19
11479283
Oncogene. 2007 Aug 13;26(37):5439-49
17694085
Chem Biol. 2010 Jan 29;17(1):65-74
20142042
Nat Chem Biol. 2010 Mar;6(3):238-243
20139990
Bioinformatics. 2006 Jun 15;22(12):1540-2
16595560
Drug Discov Today. 2009 Nov;14(21-22):1021-9
19596079
Mol Cell Biol. 2001 Sep;21(18):6091-101
11509652
Mol Cell Biol. 2002 Jul;22(13):4723-38
12052880
Mol Cell. 2008 Dec 5;32(5):718-26
19061646
Cell. 1998 Feb 6;92(3):291-4
9476889
Int J Cancer. 2007 Sep 1;121(5):1138-48
17455259
Leukemia. 2008 May;22(5):1026-34
18256683
Nat Protoc. 2007;2(6):1445-57
17545981
Nature. 1998 Oct 29;395(6705):917-21
9804427