title: On the inhibition of histone deacetylase 8.
abstract: Histone deacetylases are key regulators of gene expression and have recently emerged as important therapeutic targets for cancer and a growing number of non-malignant diseases. Many widely studied inhibitors of HDACs such as SAHA are thought to have low selectivity within or between the human HDAC isoform classes. Using an isoform-selective assay, we have shown that a number of the known inhibitors have in fact a low activity against HDAC8. Based on the wealth of structural information available for human HDAC8, we use a combination of docking and molecular dynamics simulations to determine the structural origin of the experimental results. A close relationship is found between the activity and the high surface malleability of HDAC8. These results provide a rationale for the recently described 'linkerless' HDAC8 selective inhibitors and design criteria for HDAC8 selective inhibitors.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670, USA.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Estiu
authors.forename: Nathan
authors.initials: N
authors.lastname: West
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Edward
authors.initials: E
authors.lastname: Greenberg
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
mesh_terms: D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Org Lett. 2003 Aug 21;5(17):3053-6
references.pmid: 12916979
references.citation: J Med Chem. 2008 Sep 25;51(18):5542-51
references.pmid: 18729444
references.citation: Nature. 1999 Sep 9;401(6749):188-93
references.pmid: 10490031
references.citation: Cell. 2003 Dec 12;115(6):727-38
references.pmid: 14675537
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15064-9
references.pmid: 15477595
references.citation: J Biotechnol. 2006 Jun 25;124(1):258-70
references.pmid: 16567013
references.citation: Biochemistry. 2008 Dec 23;47(51):13554-63
references.pmid: 19053282
references.citation: Bioorg Med Chem Lett. 2008 Feb 1;18(3):973-8
references.pmid: 18182289
references.citation: Curr Med Chem Anticancer Agents. 2005 Sep;5(5):529-60
references.pmid: 16178777
references.citation: Nat Chem Biol. 2010 Mar;6(3):238-243
references.pmid: 20139990
references.citation: Cell Cycle. 2005 Apr;4(4):549-51
references.pmid: 15738652
references.citation: J Med Chem. 2005 May 5;48(9):3344-53
references.pmid: 15857140
references.citation: Mol Cell Biol. 2005 Apr;25(8):2873-84
references.pmid: 15798178
references.citation: Leukemia. 2008 May;22(5):1026-34
references.pmid: 18256683
references.citation: Int J Cancer. 2004 Nov 1;112(2):171-8
references.pmid: 15352027
references.citation: Nat Rev Cancer. 2006 Jan;6(1):38-51
references.pmid: 16397526
references.citation: Cancer Chemother Pharmacol. 2001 Aug;48 Suppl 1:S17-9
references.pmid: 11587360
references.citation: Clin Cancer Res. 2004 Aug 1;10(15):5271-81
references.pmid: 15297431
references.citation: J Comput Chem. 2004 Jul 15;25(9):1157-74
references.pmid: 15116359
references.citation: Bioorg Med Chem Lett. 2007 May 15;17(10):2874-8
references.pmid: 17346959
references.citation: J Med Chem. 2008 Mar 27;51(6):1505-29
references.pmid: 18247554
references.citation: Nat Rev Cancer. 2006 Feb;6(2):107-16
references.pmid: 16491070
references.citation: J Med Chem. 2009 Nov 26;52(22):7003-13
references.pmid: 19886628
references.citation: Bioorg Med Chem Lett. 2007 Aug 15;17(16):4562-7
references.pmid: 17576064
references.citation: J Med Chem. 2006 Oct 19;49(21):6177-96
references.pmid: 17034125
references.citation: J Med Chem. 2004 Jun 17;47(13):3409-17
references.pmid: 15189037
references.citation: Structure. 2004 Jul;12(7):1325-34
references.pmid: 15242608
references.citation: J Clin Oncol. 2005 Jun 10;23(17):3971-93
references.pmid: 15897549
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4389-94
references.pmid: 12677000
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):87-92
references.pmid: 11134513
references.citation: J Med Chem. 2008 May 22;51(10):2898-906
references.pmid: 18412327
references.citation: Med Res Rev. 2005 May;25(3):261-309
references.pmid: 15717297
references.citation: J Med Chem. 2003 Nov 20;46(24):5097-116
references.pmid: 14613312
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9459-64
references.pmid: 10449714
references.citation: J Mol Biol. 2004 Apr 16;338(1):17-31
references.pmid: 15050820
references.citation: Cancer Biol Ther. 2003 Jan-Feb;2(1):30-7
references.pmid: 12673114
references.citation: Cell Cycle. 2004 Jun;3(6):779-88
references.pmid: 15153801
references.citation: J Mol Biol. 2005 Nov 18;354(1):107-20
references.pmid: 16242151
references.citation: J Med Chem. 2005 Nov 3;48(22):6936-47
references.pmid: 16250652
references.citation: Cancer Res. 2006 Jul 1;66(13):6785-92
references.pmid: 16818655
references.citation: Genes Dev. 2004 Oct 1;18(19):2315-35
references.pmid: 15466484
references.citation: Protein Sci. 2003 Nov;12(11):2443-52
references.pmid: 14573858
references.citation: J Chem Inf Model. 2009 Dec;49(12):2774-85
references.pmid: 19947584
references.citation: EMBO Rep. 2007 Sep;8(9):879-84
references.pmid: 17721440