histone deacetylase 6 | 3.5.1.- Histone deacetylases (HDACs) | IUPHAR/BPS Guide to PHARMACOLOGY

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histone deacetylase 6

target has curated data in GtoImmuPdb

Target id: 2618

Nomenclature: histone deacetylase 6

Family: 3.5.1.- Histone deacetylases (HDACs)

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1215 Xp11.23 HDAC6 histone deacetylase 6 11
Mouse - 1149 X A1.1 Hdac6 histone deacetylase 6
Rat - - Xq13 Hdac6 histone deacetylase 6
Previous and Unofficial Names
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Enzyme Reaction
EC Number:

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

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bufexamac Hs Inhibition 5.0 pKd 3
pKd 5.0 (Kd 1.07x10-5 M) [3]
scriptaid Hs Inhibition 9.6 pKi 6
pKi 9.6 (Ki 2.5x10-10 M) [6]
marbostat-100 Hs Inhibition 9.1 pKi 31
pKi 9.1 (Ki 7x10-10 M) [31]
Description: In vitro biochemical assay using recombinant purified human HDAC6.
trichostatin A Hs Inhibition 9.0 pKi 6
pKi 9.0 (Ki 1x10-9 M) [6]
vorinostat Hs Inhibition 8.8 pKi 6
pKi 8.8 (Ki 1.6x10-9 M) [6]
belinostat Hs Inhibition 8.8 pKi 6
pKi 8.8 (Ki 1.6x10-9 M) [6]
givinostat Hs Inhibition 8.4 pKi 6
pKi 8.4 (Ki 4.2x10-9 M) [6]
romidepsin Hs Inhibition 8.0 pKi 6
pKi 8.0 (Ki 9.5x10-9 M) [6]
dacinostat Hs Inhibition 8.0 pKi 6
pKi 8.0 (Ki 9.5x10-9 M) [6]
NQN-1 Hs Inhibition 5.9 pKi 15
pKi 5.9 (Ki 1.3x10-6 M) [15]
givinostat Hs Inhibition 7.6 pEC50 17
pEC50 7.6 (EC50 2.7x10-8 M) [17]
panobinostat Hs Inhibition 7.2 pEC50 17
pEC50 7.2 (EC50 6.1x10-8 M) [17]
belinostat Hs Inhibition 7.1 pEC50 17
pEC50 7.1 (EC50 8.2x10-8 M) [17]
suprastat Hs Inhibition 9.4 pIC50 22
pIC50 9.4 (IC50 4x10-10 M) [22]
nexturastat A Hs Inhibition 8.3 – 9.3 pIC50 5,22
pIC50 9.3 (IC50 5x10-10 M) [22]
pIC50 8.3 (IC50 5.02x10-9 M) [5]
ACY-738 Hs Inhibition 8.8 pIC50 16
pIC50 8.8 (IC50 1.7x10-9 M) [16]
BML-281 Hs Inhibition >8.7 pIC50 19
pIC50 >8.7 (IC50 <2x10-9 M) [19]
citarinostat Hs Inhibition 8.6 pIC50 14
pIC50 8.6 (IC50 2.6x10-9 M) [14]
tubacin Hs Inhibition 8.4 pIC50 13
pIC50 8.4 (IC50 4x10-9 M) [13]
martinostat Hs Inhibition 8.4 pIC50 35
pIC50 8.4 (IC50 4.1x10-9 M) [35]
ricolinostat Hs Inhibition 8.3 pIC50 30
pIC50 8.3 (IC50 4.7x10-9 M) [30]
CUDC-101 Hs Inhibition 8.3 pIC50 7
pIC50 8.3 (IC50 5.1x10-9 M) [7]
KA1010 Hs Inhibition 8.1 pIC50 9
pIC50 8.1 (IC50 8x10-9 M) [9]
SS-208 Hs Inhibition 7.9 pIC50 32
pIC50 7.9 (IC50 1.2x10-8 M) [32]
tubastatin A Hs Inhibition 7.8 pIC50 18
pIC50 7.8 (IC50 1.4x10-8 M) [18]
compound 16 [PMID: 20947351] Hs Inhibition 7.6 pIC50 12
pIC50 7.6 (IC50 2.6x10-8 M) [12]
fimepinostat Hs Inhibition 7.6 pIC50 27
pIC50 7.6 (IC50 2.7x10-8 M) [27]
compound 7d [PMID: 19111466] Hs Inhibition 7.4 pIC50 34
pIC50 7.4 (IC50 4x10-8 M) [34]
bavarostat Hs Inhibition 7.2 pIC50 26
pIC50 7.2 (IC50 6x10-8 M) [26]
resminostat Hs Inhibition 7.1 pIC50 20
pIC50 7.1 (IC50 7.18x10-8 M) [20]
quisinostat Hs Inhibition 7.1 pIC50 2
pIC50 7.1 (IC50 7.68x10-8 M) [2]
santacruzamate A Hs Inhibition 6.4 pIC50 25
pIC50 6.4 (IC50 4.34x10-7 M) [25]
CHR-3996 Hs Inhibition 5.7 pIC50 21
pIC50 5.7 (IC50 2.1x10-6 M) [21]
droxinostat Hs Inhibition 5.6 pIC50 37
pIC50 5.6 (IC50 2.47x10-6 M) [37]
Inhibitor Comments
HDAC6 selective inhibitors have been reported [12,15,34].
Immunopharmacology Comments
Accumulating evidence indicates that non-selective HDAC inhibitors exhibit immunosuppressive/anti-inflammatory activity in vitro and in vivo, and have potential as a drug class with uses in immune and inflammatory diseases [4,10,28-29,33], including prevention of transplant rejection [9]. For example, experimental evidence, albeit principally from murine studies, suggests that HDACs -2, -3, -6, -9 and -10 are notably involved in chronic intestinal inflammation [10], and some of the class I and class IIb HDAC isoforms are implicated in rheumatoid artiritis pathology [1]. The search for isoform-selective drug-like inhibitors with immunosuppressive activity is underway. For example, the selective HDAC6 inhibitor KA1010 has shown promise in experimental transplant models [9], and the HDAC3/6 inhibitor BML-281 has demonstrated anti-inflammatory activity in a murine model of colonic inflammation [8]. An HDAC6-selective inhibitor called CKD-L (structure not yet disclosed) has shown potential for therapeutic efficacy in studies using PBMCs isolated from patients with rheumatoid arthritis [23].
Immuno Process Associations
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0000209 protein polyubiquitination IEA
Physiological Consequences of Altering Gene Expression
Overexpression of HDAC6 induces pro-inflammatory responses.
Species:  Mouse
Tissue:  RAW 264.7 cells, primary mouse macrophages.
Technique:  Transient transfection.
References:  38
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. It has several features that make it unique amongst the other zinc-dependent HDACs (HDAC1-11). HDAC6 does not extensively associate with transcription factors, and acts as a deacetylase on non-histone proteins, including α-tubulin, HSP90, cortactin, and peroxiredoxins [24,36]. 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 misfolded protein accumulation, such as Alzheimer's and prion diseases [4,39], and has potential immunosuppressive activity. Ricolinostat (ACY-1215) and citarinostat (ACY-241) are two HDAC6-selective inhibitors in clinical trial.


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1. Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, García S, Malvar Fernandez B, McKinsey TA, Tak PP, Fossati G et al.. (2017) Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann. Rheum. Dis., 76 (1): 277-285. [PMID:27457515]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. Do A, Reid RC, Lohman RJ, Sweet MJ, Fairlie DP, Iyer A. (2017) An HDAC6 Inhibitor Confers Protection and Selectively Inhibits B-Cell Infiltration in DSS-Induced Colitis in Mice. J. Pharmacol. Exp. Ther., 360 (1): 140-151. [PMID:27827303]

9. Ellis JD, Neil DA, Inston NG, Jenkinson E, Drayson MT, Hampson P, Shuttleworth SJ, Ready AR, Cobbold M. (2016) Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation. Transplantation, 100 (8): 1667-74. [PMID:27222932]

10. Felice C, Lewis A, Armuzzi A, Lindsay JO, Silver A. (2015) Review article: selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases. Aliment. Pharmacol. Ther., 41 (1): 26-38. [PMID:25367825]

11. 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]

12. 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]

13. 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]

14. Huang P, Almeciga-Pinto I, Jarpe M, van Duzer JH, Mazitschek R, Yang M, Jones SS, Quayle SN. (2017) Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. Oncotarget, 8 (2): 2694-2707. [PMID:27926524]

15. 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]

16. Jochems J, Boulden J, Lee BG, Blendy JA, Jarpe M, Mazitschek R, Van Duzer JH, Jones S, Berton O. (2014) Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology, 39 (2): 389-400. [PMID:23954848]

17. 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]

18. Kozikowski A, Butler KV, Kalin JH. (2014) HDAC inhibitors and therapeutic methods of using same. Patent number: US8748451. Assignee: The Board Of Trustees Of The University Of Illinois. Priority date: 22/07/2009. Publication date: 10/06/2014.

19. Kozikowski AP, Tapadar S, Luchini DN, Kim KH, Billadeau DD. (2008) Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6. J. Med. Chem., 51 (15): 4370-3. [PMID:18642892]

20. 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]

21. 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]

22. Noonepalle S, Shen S, Ptáček J, Tavares MT, Zhang G, Stránský J, Pavlíček J, Ferreira GM, Hadley M, Pelaez G et al.. (2020) Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models. J. Med. Chem., [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.0c00567 [PMID:32815366]

23. Oh BR, Suh DH, Bae D, Ha N, Choi YI, Yoo HJ, Park JK, Lee EY, Lee EB, Song YW. (2017) Therapeutic effect of a novel histone deacetylase 6 inhibitor, CKD-L, on collagen-induced arthritis in vivo and regulatory T cells in rheumatoid arthritis in vitro. Arthritis Res. Ther., 19 (1): 154. [PMID:28673326]

24. Parmigiani RB, Xu WS, Venta-Perez G, Erdjument-Bromage H, Yaneva M, Tempst P, Marks PA. (2008) HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc. Natl. Acad. Sci. U.S.A., 105 (28): 9633-8. [PMID:18606987]

25. 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]

26. Porter NJ, Osko JD, Diedrich D, Kurz T, Hooker JM, Hansen FK, Christianson DW. (2018) Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity. J. Med. Chem., 61 (17): 8054-8060. [PMID:30118224]

27. 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]

28. Ren Y, Su X, Kong L, Li M, Zhao X, Yu N, Kang J. (2016) Therapeutic effects of histone deacetylase inhibitors in a murine asthma model. Inflamm. Res., 65 (12): 995-1008. [PMID:27565183]

29. Royce SG, Karagiannis TC. (2014) Histone deacetylases and their inhibitors: new implications for asthma and chronic respiratory conditions. Curr Opin Allergy Clin Immunol, 14 (1): 44-8. [PMID:24322009]

30. 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. Blood, 119 (11): 2579-89. [PMID:22262760]

31. Sellmer A, Stangl H, Beyer M, Grünstein E, Leonhardt M, Pongratz H, Eichhorn E, Elz S, Striegl B, Jenei-Lanzl Z et al.. (2018) Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors. J. Med. Chem., 61 (8): 3454-3477. [PMID:29589441]

32. Shen S, Hadley M, Ustinova K, Pavlicek J, Knox T, Noonepalle S, Tavares MT, Zimprich CA, Zhang G, Robers MB et al.. (2019) Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models. J. Med. Chem., 62 (18): 8557-8577. [PMID:31414801]

33. Shuttleworth SJ, Bailey SG, Townsend PA. (2010) Histone Deacetylase inhibitors: new promise in the treatment of immune and inflammatory diseases. Curr Drug Targets, 11 (11): 1430-8. [PMID:20583972]

34. 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]

35. Wang C, Schroeder FA, Wey HY, Borra R, Wagner FF, Reis S, Kim SW, Holson EB, Haggarty SJ, Hooker JM. (2014) In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs. J. Med. Chem., 57 (19): 7999-8009. [PMID:25203558]

36. Witt O, Deubzer HE, Milde T, Oehme I. (2009) HDAC family: What are the cancer relevant targets?. Cancer Lett., 277 (1): 8-21. [PMID:18824292]

37. 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]

38. Youn GS, Lee KW, Choi SY, Park J. (2016) Overexpression of HDAC6 induces pro-inflammatory responses by regulating ROS-MAPK-NF-κB/AP-1 signaling pathways in macrophages. Free Radic. Biol. Med., 97: 14-23. [PMID:27208785]

39. 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. Aging, 37: 91-102. [PMID:26507311]

How to cite this page

3.5.1.- Histone deacetylases (HDACs): histone deacetylase 6. Last modified on 07/09/2020. Accessed on 29/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2618.