histone deacetylase 6

Target id: 2618

Nomenclature: histone deacetylase 6

Family: 3.5.1.- Histone deacetylases (HDACs)

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for histone deacetylase 6 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1215 Xp11.23 HDAC6 histone deacetylase 6 7
Mouse - 1149 X A1.1 Hdac6 histone deacetylase 6
Rat - - Xq13 Hdac6 histone deacetylase 6
Previous and Unofficial Names
HD6
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.5.1.98

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
bufexamac Hs Inhibition 5.0 pKd 2
pKd 5.0 (Kd 1.07x10-5 M) [2]
scriptaid Hs Inhibition 9.6 pKi 5
pKi 9.6 (Ki 2.5x10-10 M) [5]
trichostatin A Hs Inhibition 9.0 pKi 5
pKi 9.0 (Ki 1x10-9 M) [5]
vorinostat Hs Inhibition 8.8 pKi 5
pKi 8.8 (Ki 1.6x10-9 M) [5]
belinostat Hs Inhibition 8.8 pKi 5
pKi 8.8 (Ki 1.6x10-9 M) [5]
givinostat Hs Inhibition 8.4 pKi 5
pKi 8.4 (Ki 4.2x10-9 M) [5]
romidepsin Hs Inhibition 8.0 pKi 5
pKi 8.0 (Ki 9.5x10-9 M) [5]
dacinostat Hs Inhibition 8.0 pKi 5
pKi 8.0 (Ki 9.5x10-9 M) [5]
NQN-1 Hs Inhibition 5.9 pKi 11
pKi 5.9 (Ki 1.3x10-6 M) [11]
givinostat Hs Inhibition 7.6 pEC50 12
pEC50 7.6 (EC50 2.7x10-8 M) [12]
panobinostat Hs Inhibition 7.2 pEC50 12
pEC50 7.2 (EC50 6.1x10-8 M) [12]
belinostat Hs Inhibition 7.1 pEC50 12
pEC50 7.1 (EC50 8.2x10-8 M) [12]
citarinostat Hs Inhibition 8.6 pIC50 10
pIC50 8.6 (IC50 2.6x10-9 M) [10]
tubacin Hs Inhibition 8.4 pIC50 9
pIC50 8.4 (IC50 4x10-9 M) [9]
ricolinostat Hs Inhibition 8.3 pIC50 17
pIC50 8.3 (IC50 4.7x10-9 M) [17]
nexturastat A Hs Inhibition 8.3 pIC50 4
pIC50 8.3 (IC50 5.02x10-9 M) [4]
CUDC-101 Hs Inhibition 8.3 pIC50 6
pIC50 8.3 (IC50 5.1x10-9 M) [6]
compound 16 [PMID: 20947351] Hs Inhibition 7.6 pIC50 8
pIC50 7.6 (IC50 2.6x10-8 M) [8]
CUDC-907 Hs Inhibition 7.6 pIC50 16
pIC50 7.6 (IC50 2.7x10-8 M) [16]
compound 7d [PMID: 19111466] Hs Inhibition 7.4 pIC50 18
pIC50 7.4 (IC50 4x10-8 M) [18]
resminostat Hs Inhibition 7.1 pIC50 13
pIC50 7.1 (IC50 7.18x10-8 M) [13]
quisinostat Hs Inhibition 7.1 pIC50 1
pIC50 7.1 (IC50 7.68x10-8 M) [1]
santacruzamate A Hs Inhibition 6.4 pIC50 15
pIC50 6.4 (IC50 4.34x10-7 M) [15]
CHR-3996 Hs Inhibition 5.7 pIC50 14
pIC50 5.7 (IC50 2.1x10-6 M) [14]
droxinostat Hs Inhibition 5.6 pIC50 19
pIC50 5.6 (IC50 2.47x10-6 M) [19]
Inhibitor Comments
HDAC6 selective inhibitors have been reported [8,11,18].
Clinically-Relevant Mutations and Pathophysiology
Disease:  Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia
Synonyms: X-linked dominant chondrodysplasia, Chassaing-Lacombe type [Orphanet: ORPHA163966]
OMIM: 300863
Orphanet: ORPHA163966
General Comments
HDAC6 is a Class II histone deacetylase. HDAC6 is required for aggresome formation and for survival of stressed cells generating ubiquitinated misfolded proteins. The aggresome is an essential element that contributes to the survival of cancer cells, hence HDAC6 is being investigated as an oncology drug target. Pharmacological modulation of HDAC6 activity may also be of use in neurodegenerative diseases caused by mis-folded protein acummulation, such as Alzheimer's and prion diseases [3,20]. Ricolinostat (ACY-1215) and citarinostat (ACY-241) are two HDAC6-selective inhibitors in clinical trial.

References

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1. Arts J, King P, Mariën A, Floren W, Beliën A, Janssen L, Pilatte I, Roux B, Decrane L, Gilissen R et al.. (2009) JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin. Cancer Res.15 (22): 6841-51. [PMID:19861438]

2. Bantscheff M, Hopf C, Savitski MM, Dittmann A, Grandi P, Michon AM, Schlegl J, Abraham Y, Becher I, Bergamini G et al.. (2011) Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol.29 (3): 255-65. [PMID:21258344]

3. Batchu SN, Brijmohan AS, Advani A. (2016) The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease. Clin. Sci.130 (12): 987-1003. [PMID:27154743]

4. Bergman JA, Woan K, Perez-Villarroel P, Villagra A, Sotomayor EM, Kozikowski AP. (2012) Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. J. Med. Chem.55 (22): 9891-9. [PMID:23009203]

5. Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R. (2010) Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol.6 (3): 238-243. [PMID:20139990]

6. Cai X, Zhai HX, Wang J, Forrester J, Qu H, Yin L, Lai CJ, Bao R, Qian C. (2010) Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem.53 (5): 2000-9. [PMID:20143778]

7. Grozinger CM, Hassig CA, Schreiber SL. (1999) Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl. Acad. Sci. U.S.A.96 (9): 4868-73. [PMID:10220385]

8. Gupta PK, Reid RC, Liu L, Lucke AJ, Broomfield SA, Andrews MR, Sweet MJ, Fairlie DP. (2010) Inhibitors selective for HDAC6 in enzymes and cells. Bioorg. Med. Chem. Lett.20 (23): 7067-70. [PMID:20947351]

9. Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl. Acad. Sci. U.S.A.100 (8): 4389-94. [PMID:12677000]

10. Huang P, Almeciga-Pinto I, Jarpe M, van Duzer JH, Mazitschek R, Yang M, Jones SS, Quayle SN. (2016) Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. Oncotarget,  [Epub ahead of print]. [PMID:27926524]

11. Inks ES, Josey BJ, Jesinkey SR, Chou CJ. (2012) A novel class of small molecule inhibitors of HDAC6. ACS Chem. Biol.7 (2): 331-9. [PMID:22047054]

12. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, Qian X, Mills E, Berghs SC, Carey N et al.. (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem. J.409 (2): 581-9. [PMID:17868033]

13. Mandl-Weber S, Meinel FG, Jankowsky R, Oduncu F, Schmidmaier R, Baumann P. (2010) The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br. J. Haematol.149 (4): 518-28. [PMID:20201941]

14. Moffat D, Patel S, Day F, Belfield A, Donald A, Rowlands M, Wibawa J, Brotherton D, Stimson L, Clark V et al.. (2010) Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor. J. Med. Chem.53 (24): 8663-78. [PMID:21080647]

15. Pavlik CM, Wong CY, Ononye S, Lopez DD, Engene N, McPhail KL, Gerwick WH, Balunas MJ. (2013) Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp. J. Nat. Prod.76 (11): 2026-33. [PMID:24164245]

16. Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M et al.. (2012) Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin. Cancer Res.18 (15): 4104-13. [PMID:22693356]

17. Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, Jarpe M, van Duzer JH, Mazitschek R, Ogier WC et al.. (2012) Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood119 (11): 2579-89. [PMID:22262760]

18. Smil DV, Manku S, Chantigny YA, Leit S, Wahhab A, Yan TP, Fournel M, Maroun C, Li Z, Lemieux AM et al.. (2009) Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg. Med. Chem. Lett.19 (3): 688-92. [PMID:19111466]

19. Wood TE, Dalili S, Simpson CD, Sukhai MA, Hurren R, Anyiwe K, Mao X, Suarez Saiz F, Gronda M, Eberhard Y et al.. (2010) Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands. Mol. Cancer Ther.9 (1): 246-56. [PMID:20053768]

20. Zhu T, Zhao D, Song Z, Yuan Z, Li C, Wang Y, Zhou X, Yin X, Hassan MF, Yang L. (2016) HDAC6 alleviates prion peptide-mediated neuronal death via modulating PI3K-Akt-mTOR pathway. Neurobiol. Aging37: 91-102. [PMID:26507311]

How to cite this page

3.5.1.- Histone deacetylases (HDACs): histone deacetylase 6. Last modified on 08/06/2017. Accessed on 23/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2618.