Target General Infomation
Target ID
T22274
Former ID
TTDNC00542
Target Name
Histone deacetylase 6
Gene Name
HDAC6
Synonyms
HD6; Histone deacetylase 6; HDAC6
Target Type
Clinical Trial
Disease Autoimmune diabetes [ICD10: E08-E13]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Multiple myeloma [ICD9: 203; ICD10: C90]
Function
In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins andtarget them to the aggresome, facilitating their clearance by autophagy.
BioChemical Class
Carbon-nitrogen hydrolase
Target Validation
T35206
UniProt ID
EC Number
EC 3.5.1.98
Sequence
MTSTGQDSTTTRQRRSRQNPQSPPQDSSVTSKRNIKKGAVPRSIPNLAEVKKKGKMKKLG
QAMEEDLIVGLQGMDLNLEAEALAGTGLVLDEQLNEFHCLWDDSFPEGPERLHAIKEQLI
QEGLLDRCVSFQARFAEKEELMLVHSLEYIDLMETTQYMNEGELRVLADTYDSVYLHPNS
YSCACLASGSVLRLVDAVLGAEIRNGMAIIRPPGHHAQHSLMDGYCMFNHVAVAARYAQQ
KHRIRRVLIVDWDVHHGQGTQFTFDQDPSVLYFSIHRYEQGRFWPHLKASNWSTTGFGQG
QGYTINVPWNQVGMRDADYIAAFLHVLLPVALEFQPQLVLVAAGFDALQGDPKGEMAATP
AGFAQLTHLLMGLAGGKLILSLEGGYNLRALAEGVSASLHTLLGDPCPMLESPGAPCRSA
QASVSCALEALEPFWEVLVRSTETVERDNMEEDNVEESEEEGPWEPPVLPILTWPVLQSR
TGLVYDQNMMNHCNLWDSHHPEVPQRILRIMCRLEELGLAGRCLTLTPRPATEAELLTCH
SAEYVGHLRATEKMKTRELHRESSNFDSIYICPSTFACAQLATGAACRLVEAVLSGEVLN
GAAVVRPPGHHAEQDAACGFCFFNSVAVAARHAQTISGHALRILIVDWDVHHGNGTQHMF
EDDPSVLYVSLHRYDHGTFFPMGDEGASSQIGRAAGTGFTVNVAWNGPRMGDADYLAAWH
RLVLPIAYEFNPELVLVSAGFDAARGDPLGGCQVSPEGYAHLTHLLMGLASGRIILILEG
GYNLTSISESMAACTRSLLGDPPPLLTLPRPPLSGALASITETIQVHRRYWRSLRVMKVE
DREGPSSSKLVTKKAPQPAKPRLAERMTTREKKVLEAGMGKVTSASFGEESTPGQTNSET
AVVALTQDQPSEAATGGATLAQTISEAAIGGAMLGQTTSEEAVGGATPDQTTSEETVGGA
ILDQTTSEDAVGGATLGQTTSEEAVGGATLAQTTSEAAMEGATLDQTTSEEAPGGTELIQ
TPLASSTDHQTPPTSPVQGTTPQISPSTLIGSLRTLELGSESQGASESQAPGEENLLGEA
AGGQDMADSMLMQGSRGLTDQAIFYAVTPLPWCPHLVAVCPIPAAGLDVTQPCGDCGTIQ
ENWVCLSCYQVYCGRYINGHMLQHHGNSGHPLVLSYIDLSAWCYYCQAYVHHQALLDVKN
IAHQNKFGEDMPHPH
Structure
3C5K; 3GV4; 3PHD
Drugs and Mode of Action
Drug(s) ACY-1215 Drug Info Phase 1/2 Autoimmune diabetes [524684], [542040]
Inhibitor (E)-8-Biphenyl-4-yl-1-oxazol-2-yl-oct-7-en-1-one Drug Info [526871]
(S)-2-Amino-N-cyclopentyl-7-mercaptoheptanamide Drug Info [529093]
2-(methylsulfonylthio)ethyl 2-propylpentanoate Drug Info [529333]
4-Benzoylamino-N-hydroxy-benzamide Drug Info [527691]
4-Butyrylamino-N-hydroxy-benzamide Drug Info [526922]
4-Chloro-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info [526878]
4-Dimethylamino-N-(6-mercapto-hexyl)-benzamide Drug Info [527439]
4-Hydroxy-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info [526266]
4-Phenylbutyrohydroxamic acid Drug Info [530700]
5-(4-Chloro-phenyl)-pentanoic acid hydroxyamide Drug Info [527056]
5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione Drug Info [529333]
5-Mercapto-pentanoic acid phenylamide Drug Info [527439]
6-(2-Bromo-acetylamino)-hexanoic acid phenylamide Drug Info [527439]
6-(9H-carbazol-9-yl)-N-hydroxyhexanamide Drug Info [531216]
6-benzenesulfinylhexanoic acid hydroxamide Drug Info [527980]
6-benzenesulfonylhexanoic acid hydroxamide Drug Info [527980]
6-Mercapto-hexanoic acid phenylamide Drug Info [527439]
6-Phenoxy-hexane-1-thiol Drug Info [527439]
6-phenylsulfanylhexanoic acid hydroxamide Drug Info [527980]
7-(Biphenyl-3-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [526871]
7-(Biphenyl-4-yloxy)-1,1,1-trifluoro-heptan-2-one Drug Info [526878]
7-(Biphenyl-4-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [526871]
7-(Naphthalen-2-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [526871]
7-Mercapto-heptanoic acid benzothiazol-2-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid biphenyl-3-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid biphenyl-4-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid phenylamide Drug Info [527439]
7-Mercapto-heptanoic acid pyridin-3-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid quinolin-3-ylamide Drug Info [527439]
7-mercapto-N-(4-phenylthiazol-2-yl)heptanamide Drug Info [529093]
8-(Biphenyl-4-yloxy)-1,1,1-trifluoro-octan-2-one Drug Info [526871]
8-Mercapto-octanoic acid phenylamide Drug Info [527439]
8-Oxo-8-phenyl-octanoic acid Drug Info [526266]
8-Oxo-8-phenyl-octanoic acid hydroxyamide Drug Info [526878]
9,9,9-Trifluoro-8-oxo-nonanoic acid phenylamide Drug Info [526878]
9-(Biphenyl-4-yloxy)-1,1,1-trifluoro-nonan-2-one Drug Info [526878]
compound 16 Drug Info [531216]
compound 7d Drug Info [529889]
Cyclo(-L-Am7(S2Py)-A2in-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ala-D-Tic-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ph4-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ph5-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Phe-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Phg-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ser(Bzl)-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ser-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-D-2MePhe-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-D-A1in-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-L-2MePhe-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-L-A1in-L-Ala-D-Pro-) Drug Info [529054]
Cyclostellettamine derivative Drug Info [527058]
droxinostat Drug Info [530619]
IKH-25 Drug Info [543662]
N-(2-Mercapto-ethyl)-N'-phenyl-oxalamide Drug Info [527500]
N-(2-Mercapto-ethyl)-N'-phenyl-succinamide Drug Info [527500]
N-(5-Hydroxycarbamoyl-pentyl)-4-nitro-benzamide Drug Info [526878]
N-(6-Hydroxycarbamoyl-hexyl)-benzamide Drug Info [526266]
N-(6-Mercapto-hexyl)-benzamide Drug Info [527439]
N-(biphenyl-3-yl)-6-(sulfamoylamino)hexanamide Drug Info [529866]
N-(quinolin-3-yl)-6-(sulfamoylamino)hexanamide Drug Info [529866]
N-(quinolin-6-yl)-6-(sulfamoylamino)hexanamide Drug Info [529866]
N-(quinolin-8-yl)-6-(sulfamoylamino)hexanamide Drug Info [529866]
N-Hydroxy-4-((R)-2-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-((S)-2-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(2-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(3-phenyl-propionylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(4-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(5-phenyl-pentanoylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(pentanoylamino-methyl)-benzamide Drug Info [526922]
N-Hydroxy-4-(phenylacetylamino-methyl)-benzamide Drug Info [526922]
N-Hydroxy-4-phenylacetylamino-benzamide Drug Info [527691]
N-phenyl-6-(sulfamoylamino)hexanamide Drug Info [529866]
N-[5-(Formyl-hydroxy-amino)-pentyl]-benzamide Drug Info [526917]
N1-(biphenyl-3-yl)-N8-hydroxyoctanediamide Drug Info [529866]
N1-(biphenyl-4-yl)-N8-hydroxyoctanediamide Drug Info [530106]
N1-hydroxy-N8-(4-phenylthiazol-2-yl)octanediamide Drug Info [530106]
nexturastat A Drug Info [532053]
NILTUBACIN Drug Info [530700]
NQN-1 Drug Info [531683]
Octanedioic acid bis-hydroxyamide Drug Info [526376]
Octanedioic acid hydroxyamide pyridin-2-ylamide Drug Info [526266]
Octanedioic acid hydroxyamide pyridin-4-ylamide Drug Info [526266]
PSAMMAPLIN A Drug Info [526878]
santacruzamate A Drug Info [532523]
ST-2741 Drug Info [530067]
ST-2986 Drug Info [530016]
ST-2987 Drug Info [530016]
ST-3050 Drug Info [530016]
Thioacetic acid S-(6-phenylcarbamoyl-hexyl) ester Drug Info [527439]
Tubacin Drug Info [536272], [537114]
UCL-67022 Drug Info [543662]
Modulator ACY-1215 Drug Info [544487]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Alcoholism
Viral carcinogenesis
Pathway Interaction Database Signaling events mediated by HDAC Class II
Signaling events mediated by HDAC Class I
Reactome NOTCH1 Intracellular Domain Regulates Transcription
Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
Assembly of the primary cilium
WikiPathways Ectoderm Differentiation
Neural Crest Differentiation
Cell Cycle
References
Ref 524684ClinicalTrials.gov (NCT02091063) ACY-1215 for Relapsed/Refractory Lymphoid Malignancies. U.S. National Institutes of Health.
Ref 542040(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7010).
Ref 526266J Med Chem. 2002 Feb 14;45(4):753-7.Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates.
Ref 526376J Med Chem. 2002 Jul 18;45(15):3296-309.Structure-activity relationships on phenylalanine-containing inhibitors of histone deacetylase: in vitro enzyme inhibition, induction of differentiation, and inhibition of proliferation in Friend leukemic cells.
Ref 526871Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13.Heterocyclic ketones as inhibitors of histone deacetylase.
Ref 526878J Med Chem. 2003 Nov 20;46(24):5097-116.Histone deacetylase inhibitors.
Ref 526917Bioorg Med Chem Lett. 2004 Jan 19;14(2):449-53.Design, synthesis, and activity of HDAC inhibitors with a N-formyl hydroxylamine head group.
Ref 526922J Med Chem. 2004 Jan 15;47(2):467-74.Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors.
Ref 527056Bioorg Med Chem Lett. 2004 May 17;14(10):2477-81.Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides.
Ref 527058Bioorg Med Chem Lett. 2004 May 17;14(10):2617-20.Three new cyclostellettamines, which inhibit histone deacetylase, from a marine sponge of the genus Xestospongia.
Ref 527439J Med Chem. 2005 Feb 24;48(4):1019-32.Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates.
Ref 527500Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors.
Ref 527691J Med Chem. 2005 Aug 25;48(17):5530-5.Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.
Ref 527980J Med Chem. 2006 Jan 26;49(2):800-5.Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides.
Ref 529054Bioorg Med Chem. 2007 Dec 15;15(24):7830-9. Epub 2007 Aug 26.Molecular design of histone deacetylase inhibitors by aromatic ring shifting in chlamydocin framework.
Ref 529093J Med Chem. 2007 Nov 1;50(22):5425-38. Epub 2007 Oct 11.Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors.
Ref 529333Bioorg Med Chem Lett. 2008 Mar 15;18(6):1893-7. Epub 2008 Feb 8.New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity.
Ref 529866Bioorg Med Chem Lett. 2009 Jan 15;19(2):336-40. Epub 2008 Nov 27.Sulfamides as novel histone deacetylase inhibitors.
Ref 529889Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg Med Chem Lett. 2009 Feb 1;19(3):688-92.
Ref 530016Bioorg Med Chem Lett. 2009 Apr 15;19(8):2346-9. Epub 2009 Feb 12.N-Hydroxy-(4-oxime)-cinnamide: a versatile scaffold for the synthesis of novel histone deacetylase [correction of deacetilase] (HDAC)inhibitors.
Ref 530067Bioorg Med Chem Lett. 2009 May 15;19(10):2840-3. Epub 2009 Mar 26.Exploring bis-(indolyl)methane moiety as an alternative and innovative CAP group in the design of histone deacetylase (HDAC) inhibitors.
Ref 530106Bioorg Med Chem Lett. 2009 Jun 1;19(11):3023-6. Epub 2009 Apr 20.Isoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: effects on HDAC biology and antiproliferative activity.
Ref 530619Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands. Mol Cancer Ther. 2010 Jan;9(1):246-56.
Ref 530700Nat Chem Biol. 2010 Mar;6(3):238-243. Epub 2010 Feb 7.Chemical phylogenetics of histone deacetylases.
Ref 531216Bioorg Med Chem Lett. 2010 Dec 1;20(23):7067-70. Epub 2010 Oct 12.Inhibitors selective for HDAC6 in enzymes and cells.
Ref 531683A novel class of small molecule inhibitors of HDAC6. ACS Chem Biol. 2012 Feb 17;7(2):331-9.
Ref 532053Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. J Med Chem. 2012 Nov 26;55(22):9891-9.
Ref 532523Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp. J Nat Prod. 2013 Nov 22;76(11):2026-33.
Ref 536272Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006 Sep;5(9):769-84.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 543662(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2618).
Ref 544487Promising therapies in multiple myeloma. Blood. 2015 July 16; 126(3): 300-310.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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