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Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | - | 1215 | Xp11.23 | HDAC6 | histone deacetylase 6 | 12 |
| Mouse | - | 1149 | X 3.58 cM | Hdac6 | histone deacetylase 6 | |
| Rat | - | - | Xq13 | Hdac6 | histone deacetylase 6 | |
| Previous and Unofficial Names |
| HD6 |
| Database Links |
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| Alphafold | Q9UBN7 (Hs), Q9Z2V5 (Mm) |
| BRENDA | 3.5.1.98 |
| CATH/Gene3D | 3.30.40.10, 3.40.800.20 |
| ChEMBL Target | CHEMBL1865 (Hs), CHEMBL2878 (Mm) |
| DrugBank Target | Q9UBN7 (Hs) |
| Ensembl Gene | ENSG00000094631 (Hs), ENSMUSG00000031161 (Mm), ENSRNOG00000048738 (Rn) |
| Entrez Gene | 10013 (Hs), 15185 (Mm), 84581 (Rn) |
| Human Protein Atlas | ENSG00000094631 (Hs) |
| KEGG Enzyme | 3.5.1.98 |
| KEGG Gene | hsa:10013 (Hs), mmu:15185 (Mm), rno:84581 (Rn) |
| OMIM | 300272 (Hs) |
| Orphanet | ORPHA248481 (Hs) |
| Pharos | Q9UBN7 (Hs) |
| RefSeq Nucleotide | NM_006044 (Hs), NM_010413 (Mm) |
| RefSeq Protein | NP_006035 (Hs), NP_034543 (Mm) |
| SynPHARM | 79159 (in complex with trichostatin A) |
| UniProtKB | Q9UBN7 (Hs), Q9Z2V5 (Mm) |
| Wikipedia | HDAC6 (Hs) |
| Enzyme Reaction |
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Download all structure-activity data for this target as a CSV file 
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| HDAC6 selective inhibitors have been reported [13,16,37]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 [4,11,31-32,36], including prevention of transplant rejection [10]. 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 [11], 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 [10], and the HDAC3/6 inhibitor BML-281 has demonstrated anti-inflammatory activity in a murine model of colonic inflammation [9]. 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 [24]. |
| Immuno Process Associations | ||
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| Physiological Consequences of Altering Gene Expression
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| 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 [26,40]. 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 [4,46], and has potential immunosuppressive activity. Ricolinostat (ACY-1215) and citarinostat (ACY-241) are two HDAC6-selective inhibitors in clinical trial. Tenaya Therapeutics have reported preclinical evidence from their HDAC6 inhibitor TN-301 (previously TYA-11631) that indicates potential to treat the left ventricle damage that is caused by the genetic heart condition dilated cardiomyopathy, in which HDAC6 has been implicated [25]. |
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]
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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]
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15. 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]
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20. 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]
21. 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]
22. 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]
23. 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, 63 (18): 10246-10262. [PMID:32815366]
24. 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]
25. Pang X, Guan Q, Lin X, Chang N. (2023) Knockdown of HDAC6 alleviates ventricular remodeling in experimental dilated cardiomyopathy via inhibition of NLRP3 inflammasome activation and promotion of cardiomyocyte autophagy. Cell Biol Toxicol, 39 (5): 2365-2379. [PMID:35764897]
26. 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 USA, 105 (28): 9633-8. [PMID:18606987]
27. 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]
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29. 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]
30. Qiu Q, Chi F, Zhou D, Xie Z, Liu Y, Wu H, Yin Z, Shi W, Qian H. (2023) Exploration of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Bispecific Inhibitors Based on the Moiety of Fedratinib for Treatment of Both Hematologic Malignancies and Solid Cancers. J Med Chem, 66 (8): 5753-5773. [PMID:37057760]
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33. 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]
34. 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]
35. 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]
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37. 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]
38. Tsimberidou AM, Beer PA, Cartwright CA, Haymaker C, Vo HH, Kiany S, Cecil ARL, Dow J, Haque K, Silva FA et al.. (2021) Preclinical Development and First-in-Human Study of KA2507, a Selective and Potent Inhibitor of Histone Deacetylase 6, for Patients with Refractory Solid Tumors. Clin Cancer Res, 27 (13): 3584-3594. [PMID:33947698]
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41. 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]
42. 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]
43. Yu WC, Yeh TY, Ye CH, Chong PCT, Ho YH, So DK, Yap KY, Peng GR, Shao CH, Jagtap AD et al.. (2023) Discovery of HDAC6, HDAC8, and 6/8 Inhibitors and Development of Cell-Based Drug Screening Models for the Treatment of TGF-β-Induced Idiopathic Pulmonary Fibrosis. J Med Chem, 66 (15): 10528-10557. [PMID:37463500]
44. Yue K, Sun S, Jia G, Qin M, Hou X, Chou CJ, Huang C, Li X. (2022) First-in-Class Hydrazide-Based HDAC6 Selective Inhibitor with Potent Oral Anti-Inflammatory Activity by Attenuating NLRP3 Inflammasome Activation. J Med Chem, 65 (18): 12140-12162. [PMID:36073117]
45. Zhao C, Zhang Y, Zhang J, Li S, Liu M, Geng Y, Liu F, Chai Q, Meng H, Li M et al.. (2023) Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer. J Med Chem, 66 (20): 14150-14174. [PMID:37796543]
46. 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]
3.5.1.- Histone deacetylases (HDACs): histone deacetylase 6. Last modified on 22/01/2024. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2618.
target has curated data in GtoImmuPdb
