Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4YWTO)

• DTT Name: Histone deacetylase 3 (HDAC3)
• Synonyms: SMAP45; RPD32; RPD3-2; HD3
• Gene Name: HDAC3
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Carbon-nitrogen hydrolase
• UniProt ID: HDAC3_HUMAN
• TTD ID: T05090
• EC Number: EC 3.5.1.98
• Sequence:
  MAKTVAYFYDPDVGNFHYGAGHPMKPHRLALTHSLVLHYGLYKKMIVFKPYQASQHDMCR
  FHSEDYIDFLQRVSPTNMQGFTKSLNAFNVGDDCPVFPGLFEFCSRYTGASLQGATQLNN
  KICDIAINWAGGLHHAKKFEASGFCYVNDIVIGILELLKYHPRVLYIDIDIHHGDGVQEA
  FYLTDRVMTVSFHKYGNYFFPGTGDMYEVGAESGRYYCLNVPLRDGIDDQSYKHLFQPVI
  NQVVDFYQPTCIVLQCGADSLGCDRLGCFNLSIRGHGECVEYVKSFNIPLLVLGGGGYTV
  RNVARCWTYETSLLVEEAISEELPYSEYFEYFAPDFTLHPDVSTRIENQNSRQYLDQIRQ
  TIFENLKMLNHAPSVQIHDVPADLLTYDRTDEADAEERGPEENYSRPEAPNEFYDGDHDN
  DKESDVEI
• 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. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation. Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress. Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner. During the activation phase, promotes the accumulation of ubiquitinated ARNTL/BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and ARNTL/BMAL1. The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates.
• KEGG Pathway:
  Thyroid hormone signaling pathway (hsa04919)
  Alcoholism (hsa05034)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  p75NTR negatively regulates cell cycle via SC1 (R-HSA-193670)
  PPARA activates gene expression (R-HSA-1989781)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  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)
  Notch-HLH transcription pathway (R-HSA-350054)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Loss of MECP2 binding ability to the NCoR/SMRT complex (R-HSA-9022537)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  HCMV Early Events (R-HSA-9609690)
  STAT3 nuclear events downstream of ALK signaling (R-HSA-9701898)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme signaling (R-HSA-9707616)
  NR1D1 (REV-ERBA) represses gene expression (R-HSA-1368071)

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
Diaryl amine derivative 4	DMZL6AX	N. A.	N. A.	Patented	[2]
PMID29671355-Compound-11	DMNKABH	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-21	DMPJN0M	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-25	DMPV0KZ	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-31	DM3H78D	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-43	DMVPMWJ	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-44	DM80A3V	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-55	DMJV1SY	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-56	DM0VBMI	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-57	DM57N3Y	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-59	DM2F0CQ	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-61	DMXH1G3	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-62	DMWRS34	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-67	DM1RPL4	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-8	DM7YQJK	N. A.	N. A.	Patented	[3]
PMID29671355-Compound-9	DMXL96M	N. A.	N. A.	Patented	[3]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
droxinostat	DM5IA9W	Discovery agent	N.A.	Investigative	[4]
RGFP966	DME9T0A	Discovery agent	N.A.	Investigative	[5]

References

• [1] A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors. Clin Cancer Res. 2012 May 1;18(9):2687-94.
• [2] Novel histone deacetylase 6 (HDAC6) selective inhibitors: a patent evaluation (WO2014181137).Expert Opin Ther Pat. 2017 Mar;27(3):229-236.
• [3] HDAC inhibitors: a 2013-2017 patent survey.Expert Opin Ther Pat. 2018 Apr 19:1-17.
• [4] Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands. Mol Cancer Ther. 2010 Jan;9(1):246-56.
• [5] HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2647-52.