Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTSHTOI)

• DTT Name: Histone deacetylase 2 (HDAC2)
• Synonyms: HD2
• Gene Name: HDAC2
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Lymphoma [ICD-11: 2A80-2A86]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• BioChemical Class: Carbon-nitrogen hydrolase
• UniProt ID: HDAC2_HUMAN
• TTD ID: T51191
• EC Number: EC 3.5.1.98
• Sequence:
  MAYSQGGGKKKVCYYYDGDIGNYYYGQGHPMKPHRIRMTHNLLLNYGLYRKMEIYRPHKA
  TAEEMTKYHSDEYIKFLRSIRPDNMSEYSKQMQRFNVGEDCPVFDGLFEFCQLSTGGSVA
  GAVKLNRQQTDMAVNWAGGLHHAKKSEASGFCYVNDIVLAILELLKYHQRVLYIDIDIHH
  GDGVEEAFYTTDRVMTVSFHKYGEYFPGTGDLRDIGAGKGKYYAVNFPMRDGIDDESYGQ
  IFKPIISKVMEMYQPSAVVLQCGADSLSGDRLGCFNLTVKGHAKCVEVVKTFNLPLLMLG
  GGGYTIRNVARCWTYETAVALDCEIPNELPYNDYFEYFGPDFKLHISPSNMTNQNTPEYM
  EKIKQRLFENLRMLPHAPGVQMQAIPEDAVHEDSGDEDGEDPDKRISIRASDKRIACDEE
  FSDSEDEGEGGRRNVADHKKGAKKARIEEDKKETEDKKTDVKEEDKSKDNSGEKTDTKGT
  KSEQLSNP
• Function: Gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
• KEGG Pathway:
  Cell cycle (hsa04110)
  Notch signaling pathway (hsa04330)
  Thyroid hormone signaling pathway (hsa04919)
  Huntington's disease (hsa05016)
  Alcoholism (hsa05034)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  Chronic myeloid leukemia (hsa05220)
• Reactome Pathway:
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  HDACs deacetylate histones (R-HSA-3214815)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  p75NTR negatively regulates cell cycle via SC1 (R-HSA-193670)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CHR-3996	DMIXPNG	Lymphoma	2A80-2A86	Phase 1/2	[1]

16 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID29671355-Compound-11	DMNKABH	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-21	DMPJN0M	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-23	DMUBOEX	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-25	DMPV0KZ	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-31	DM3H78D	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-43	DMVPMWJ	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-44	DM80A3V	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-55	DMJV1SY	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-56	DM0VBMI	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-59	DM2F0CQ	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-61	DMXH1G3	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-62	DMWRS34	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-67	DM1RPL4	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-74	DM49YTU	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-8	DM7YQJK	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-9	DMXL96M	N. A.	N. A.	Patented	[2]

96 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(E)-8-Biphenyl-4-yl-1-oxazol-2-yl-oct-7-en-1-one	DM5LSY9	Discovery agent	N.A.	Investigative	[3]
1,1,1-Trifluoro-8-(4-phenoxy-phenoxy)-octan-2-one	DM6GI4Z	Discovery agent	N.A.	Investigative	[4]
1,1,1-Trifluoro-8-phenoxy-octan-2-one	DM41R2O	Discovery agent	N.A.	Investigative	[4]
2-(allyloxy)-N8-hydroxy-N1-phenyloctanediamide	DM6P20R	Discovery agent	N.A.	Investigative	[5]
2-(benzyloxy)-N7-hydroxy-N1-phenylheptanediamide	DM48C7G	Discovery agent	N.A.	Investigative	[5]
2-(methylsulfonylthio)ethyl 2-propylpentanoate	DMM52D3	Discovery agent	N.A.	Investigative	[6]
4-Benzoylamino-N-hydroxy-benzamide	DMYBPFS	Discovery agent	N.A.	Investigative	[7]
4-Butyrylamino-N-hydroxy-benzamide	DMRY6B4	Discovery agent	N.A.	Investigative	[8]
4-Chloro-N-(5-hydroxycarbamoyl-pentyl)-benzamide	DM5AVG3	Discovery agent	N.A.	Investigative	[9]
4-Dimethylamino-N-(6-mercapto-hexyl)-benzamide	DM0M8G5	Discovery agent	N.A.	Investigative	[10]
4-Hydroxy-N-(5-hydroxycarbamoyl-pentyl)-benzamide	DMULOHZ	Discovery agent	N.A.	Investigative	[11]
4-Phenylbutyrohydroxamic acid	DMCZKN7	Discovery agent	N.A.	Investigative	[12]
5-(4-Chloro-phenyl)-pentanoic acid hydroxyamide	DM6CRVS	Discovery agent	N.A.	Investigative	[13]
5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione	DM7KQXL	Discovery agent	N.A.	Investigative	[6]
5-(Biphenyl-4-yl)-pentanoic acid N-hydroxyamide	DMPQSZN	Discovery agent	N.A.	Investigative	[14]
5-Mercapto-pentanoic acid phenylamide	DMET3OJ	Discovery agent	N.A.	Investigative	[10]
6-(2-Bromo-acetylamino)-hexanoic acid phenylamide	DM9LKXD	Discovery agent	N.A.	Investigative	[10]
6-benzenesulfinylhexanoic acid hydroxamide	DM2I95Z	Discovery agent	N.A.	Investigative	[15]
6-benzenesulfonylhexanoic acid hydroxamide	DMY9IK8	Discovery agent	N.A.	Investigative	[15]
6-Mercapto-hexanoic acid phenylamide	DMD2FW9	Discovery agent	N.A.	Investigative	[10]
6-Phenoxy-hexane-1-thiol	DMVYIN2	Discovery agent	N.A.	Investigative	[10]
6-phenylsulfanylhexanoic acid hydroxamide	DM3OLM6	Discovery agent	N.A.	Investigative	[15]
7-(Biphenyl-3-yloxy)-1-oxazol-2-yl-heptan-1-one	DMLCGSY	Discovery agent	N.A.	Investigative	[3]
7-(Biphenyl-4-yloxy)-1,1,1-trifluoro-heptan-2-one	DM28GZ7	Discovery agent	N.A.	Investigative	[4]
7-(Biphenyl-4-yloxy)-1-oxazol-2-yl-heptan-1-one	DMY027P	Discovery agent	N.A.	Investigative	[3]
7-(Biphenyl-4-yloxy)-heptanoic acid hydroxyamide	DMO4YLA	Discovery agent	N.A.	Investigative	[16]
7-(Naphthalen-2-yloxy)-1-oxazol-2-yl-heptan-1-one	DM4VQN8	Discovery agent	N.A.	Investigative	[3]
7-Biphenyl-4-yl-heptanoic acid hydroxyamide	DMV54MT	Discovery agent	N.A.	Investigative	[17]
7-Mercapto-heptanoic acid benzothiazol-2-ylamide	DMPYTHV	Discovery agent	N.A.	Investigative	[10]
7-Mercapto-heptanoic acid biphenyl-3-ylamide	DMEQKPO	Discovery agent	N.A.	Investigative	[10]
7-Mercapto-heptanoic acid biphenyl-4-ylamide	DMJMOUK	Discovery agent	N.A.	Investigative	[10]
7-Mercapto-heptanoic acid phenylamide	DM4912P	Discovery agent	N.A.	Investigative	[10]
7-Mercapto-heptanoic acid pyridin-3-ylamide	DMQ9PLA	Discovery agent	N.A.	Investigative	[10]
7-Mercapto-heptanoic acid quinolin-3-ylamide	DMTAGJ1	Discovery agent	N.A.	Investigative	[10]
7-Phenoxy-heptanoic acid hydroxyamide	DM1FL5G	Discovery agent	N.A.	Investigative	[17]
8-(Biphenyl-3-yloxy)-1,1,1-trifluoro-octan-2-one	DMH3SDO	Discovery agent	N.A.	Investigative	[4]
8-(Biphenyl-4-yloxy)-1,1,1-trifluoro-octan-2-one	DM23XGW	Discovery agent	N.A.	Investigative	[4]
8-(Biphenyl-4-yloxy)-2-oxo-octanoic acid	DMDIGPW	Discovery agent	N.A.	Investigative	[16]
8-Mercapto-octanoic acid phenylamide	DMD3FWU	Discovery agent	N.A.	Investigative	[10]
8-Oxo-8-phenyl-octanoic acid	DMXDQ25	Discovery agent	N.A.	Investigative	[11]
8-Oxo-8-phenyl-octanoic acid hydroxyamide	DMWM1UL	Discovery agent	N.A.	Investigative	[9]
8-Phenyl-octanoic acid hydroxyamide	DM516NE	Discovery agent	N.A.	Investigative	[17]
9,9,9-Trifluoro-8-oxo-nonanoic acid phenylamide	DMVBCID	Discovery agent	N.A.	Investigative	[4]
9-(Biphenyl-4-yloxy)-1,1,1-trifluoro-nonan-2-one	DMIY3D6	Discovery agent	N.A.	Investigative	[4]
Cyclostellettamine derivative	DMFTDPQ	Discovery agent	N.A.	Investigative	[18]
KAR-1880	DMXAK75	Dermatitis	EA80-EA89	Investigative	[19]
N-(2-amino-5-(benzofuran-2-yl)phenyl)benzamide	DM7VN9P	Discovery agent	N.A.	Investigative	[20]
N-(2-amino-5-(furan-2-yl)phenyl)benzamide	DMY9HO8	Discovery agent	N.A.	Investigative	[20]
N-(2-amino-5-(furan-3-yl)phenyl)benzamide	DMI7W9N	Discovery agent	N.A.	Investigative	[20]
N-(2-amino-5-(pyridin-4-yl)phenyl)benzamide	DM1KVPG	Discovery agent	N.A.	Investigative	[20]
N-(2-amino-5-(thiazol-2-yl)phenyl)benzamide	DM2K0AJ	Discovery agent	N.A.	Investigative	[20]
N-(2-amino-5-(thiophen-2-yl)phenyl)nicotinamide	DMFYG79	Discovery agent	N.A.	Investigative	[21]
N-(2-aminophenyl)-4-methoxybenzamide	DMTKWUM	Discovery agent	N.A.	Investigative	[22]
N-(2-aminophenyl)benzamide	DM8PB90	Discovery agent	N.A.	Investigative	[20]
N-(2-aminophenyl)nicotinamide	DMRDQ1B	Discovery agent	N.A.	Investigative	[21]
N-(2-aminophenyl)quinoxaline-6-carboxamide	DMJXV7C	Discovery agent	N.A.	Investigative	[22]
N-(2-Mercapto-ethyl)-N'-phenyl-oxalamide	DM0GOPV	Discovery agent	N.A.	Investigative	[23]
N-(2-Mercapto-ethyl)-N'-phenyl-succinamide	DMJLFOQ	Discovery agent	N.A.	Investigative	[23]
N-(3'-acetyl-4-aminobiphenyl-3-yl)benzamide	DMYJB1A	Discovery agent	N.A.	Investigative	[20]
N-(4'-acetyl-4-aminobiphenyl-3-yl)benzamide	DMIJLX6	Discovery agent	N.A.	Investigative	[20]
N-(4-amino-3'-methoxybiphenyl-3-yl)benzamide	DMV6154	Discovery agent	N.A.	Investigative	[20]
N-(4-amino-3'-methylbiphenyl-3-yl)benzamide	DM910BF	Discovery agent	N.A.	Investigative	[20]
N-(4-amino-4'-bromobiphenyl-3-yl)benzamide	DMIAGS8	Discovery agent	N.A.	Investigative	[20]
N-(4-amino-4'-fluorobiphenyl-3-yl)benzamide	DMR5D16	Discovery agent	N.A.	Investigative	[20]
N-(4-amino-4'-methoxybiphenyl-3-yl)benzamide	DM93PDA	Discovery agent	N.A.	Investigative	[20]
N-(4-amino-4'-vinylbiphenyl-3-yl)benzamide	DMSUJDH	Discovery agent	N.A.	Investigative	[20]
N-(4-aminobiphenyl-3-yl)benzamide	DMLA92O	Discovery agent	N.A.	Investigative	[20]
N-(4-aminobiphenyl-3-yl)nicotinamide	DMXVZIY	Discovery agent	N.A.	Investigative	[21]
N-(4-hydroxybiphenyl-3-yl)benzamide	DMC5H8G	Discovery agent	N.A.	Investigative	[21]
N-(5-Hydroxycarbamoyl-pentyl)-4-nitro-benzamide	DMSUW7M	Discovery agent	N.A.	Investigative	[9]
N-(6-Hydroxycarbamoyl-hexyl)-benzamide	DMIZVMT	Discovery agent	N.A.	Investigative	[11]
N-(6-Mercapto-hexyl)-benzamide	DM01Y37	Discovery agent	N.A.	Investigative	[10]
N-Hydroxy-4-((R)-2-phenyl-butyrylamino)-benzamide	DMCN91A	Discovery agent	N.A.	Investigative	[7]
N-Hydroxy-4-((S)-2-phenyl-butyrylamino)-benzamide	DMVK2Y3	Discovery agent	N.A.	Investigative	[7]
N-Hydroxy-4-(2-phenyl-butyrylamino)-benzamide	DMHEQ41	Discovery agent	N.A.	Investigative	[7]
N-Hydroxy-4-(3-phenyl-propionylamino)-benzamide	DMUOCQB	Discovery agent	N.A.	Investigative	[24]
N-Hydroxy-4-(4-phenyl-butyrylamino)-benzamide	DMVEOBY	Discovery agent	N.A.	Investigative	[7]
N-Hydroxy-4-(5-phenyl-pentanoylamino)-benzamide	DMISRMT	Discovery agent	N.A.	Investigative	[7]
N-Hydroxy-4-(pentanoylamino-methyl)-benzamide	DMGTNQY	Discovery agent	N.A.	Investigative	[8]
N-Hydroxy-4-(phenylacetylamino-methyl)-benzamide	DMDUOH4	Discovery agent	N.A.	Investigative	[8]
N-Hydroxy-4-phenylacetylamino-benzamide	DMCRU17	Discovery agent	N.A.	Investigative	[7]
N-Hydroxy-E-3-(4'-chlorobiphenyl-4-yl)-acrylamide	DM3J5MR	Discovery agent	N.A.	Investigative	[14]
N-Hydroxy-E-3-(4'-cyanobiphenyl-4-yl)-acrylamide	DMVFKO4	Discovery agent	N.A.	Investigative	[14]
N-Hydroxy-E-3-(biphenyl-4-yl)-acrylamide	DMQCK5G	Discovery agent	N.A.	Investigative	[14]
N7-hydroxy-2-methoxy-N1-phenylheptanediamide	DM6XDZA	Discovery agent	N.A.	Investigative	[5]
N7-hydroxy-N1-phenyl-2-propoxyheptanediamide	DMDJUZX	Discovery agent	N.A.	Investigative	[5]
N8,2-dihydroxy-N1-phenyloctanediamide	DMHC32M	Discovery agent	N.A.	Investigative	[5]
N8-hydroxy-2-methoxy-N1-phenyloctanediamide	DM7OZ2T	Discovery agent	N.A.	Investigative	[5]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Discovery agent	N.A.	Investigative	[25]
Octanedioic acid hydroxyamide pyridin-2-ylamide	DMHNWS1	Discovery agent	N.A.	Investigative	[11]
Octanedioic acid hydroxyamide pyridin-4-ylamide	DM945RK	Discovery agent	N.A.	Investigative	[11]
PSAMMAPLIN A	DM6T0IQ	Discovery agent	N.A.	Investigative	[9]
santacruzamate A	DMFAM7P	Discovery agent	N.A.	Investigative	[26]
ST-2986	DMNERM6	Discovery agent	N.A.	Investigative	[27]
ST-2987	DMWXTM8	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
Thioacetic acid S-(6-phenylcarbamoyl-hexyl) ester	DMBOKSF	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Atopic dermatitis	EA90	Skin	8.48E-01	-7.29E-04	-4.65E-03

References

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• [2] HDAC inhibitors: a 2013-2017 patent survey.Expert Opin Ther Pat. 2018 Apr 19:1-17.
• [3] Heterocyclic ketones as inhibitors of histone deacetylase. Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13.
• [4] Trifluoromethyl ketones as inhibitors of histone deacetylase. Bioorg Med Chem Lett. 2002 Dec 2;12(23):3443-7.
• [5] Omega-alkoxy analogues of SAHA (vorinostat) as inhibitors of HDAC: a study of chain-length and stereochemical dependence. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6261-5.
• [6] New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity. Bioorg Med Chem Lett. 2008 Mar 15;18(6):1893-7.
• [7] Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. J Med Chem. 2005 Aug 25;48(17):5530-5.
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• [11] Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates. J Med Chem. 2002 Feb 14;45(4):753-7.
• [12] Chemical phylogenetics of histone deacetylases. Nat Chem Biol. 2010 Mar;6(3):238-243.
• [13] Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides. Bioorg Med Chem Lett. 2004 May 17;14(10):2477-81.
• [14] Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Eur J Med Chem. 2009 May;44(5):1900-12.
• [15] Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides. J Med Chem. 2006 Jan 26;49(2):800-5.
• [16] Alpha-keto amides as inhibitors of histone deacetylase. Bioorg Med Chem Lett. 2003 Oct 6;13(19):3331-5.
• [17] A novel series of histone deacetylase inhibitors incorporating hetero aromatic ring systems as connection units. Bioorg Med Chem Lett. 2003 Nov 3;13(21):3817-20.
• [18] Three new cyclostellettamines, which inhibit histone deacetylase, from a marine sponge of the genus Xestospongia. Bioorg Med Chem Lett. 2004 May 17;14(10):2617-20.
• [19] URL: 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: 2616).
• [20] Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett. 2010 May 15;20(10):3142-5.
• [21] Bioorg Med Chem Lett. 2008 Dec 1;18(23):6104-9. Epub 2008 Oct 14.SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2).
• [22] Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity. J Med Chem. 2007 Nov 15;50(23):5543-6.
• [23] Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors. Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.
• [24] Design, synthesis and preliminary biological evaluation of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives as novel histone deacetyla... Eur J Med Chem. 2009 Nov;44(11):4470-6.
• [25] Structure-activity relationships on phenylalanine-containing inhibitors of histone deacetylase: in vitro enzyme inhibition, induction of differenti... J Med Chem. 2002 Jul 18;45(15):3296-309.
• [26] Santacruzamate 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.
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