Target Information
Target General Information | Top | |||||
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Target ID |
T05090
(Former ID: TTDI01956)
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Target Name |
Histone deacetylase 3 (HDAC3)
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Synonyms |
SMAP45; RPD32; RPD3-2; HD3
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Gene Name |
HDAC3
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Lymphoma [ICD-11: 2A80-2A86] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
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.
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BioChemical Class |
Carbon-nitrogen hydrolase
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UniProt ID | ||||||
EC Number |
EC 3.5.1.98
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Sequence |
MAKTVAYFYDPDVGNFHYGAGHPMKPHRLALTHSLVLHYGLYKKMIVFKPYQASQHDMCR
FHSEDYIDFLQRVSPTNMQGFTKSLNAFNVGDDCPVFPGLFEFCSRYTGASLQGATQLNN KICDIAINWAGGLHHAKKFEASGFCYVNDIVIGILELLKYHPRVLYIDIDIHHGDGVQEA FYLTDRVMTVSFHKYGNYFFPGTGDMYEVGAESGRYYCLNVPLRDGIDDQSYKHLFQPVI NQVVDFYQPTCIVLQCGADSLGCDRLGCFNLSIRGHGECVEYVKSFNIPLLVLGGGGYTV RNVARCWTYETSLLVEEAISEELPYSEYFEYFAPDFTLHPDVSTRIENQNSRQYLDQIRQ TIFENLKMLNHAPSVQIHDVPADLLTYDRTDEADAEERGPEENYSRPEAPNEFYDGDHDN DKESDVEI Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T38AWT |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | CHR-3996 | Drug Info | Phase 1/2 | Lymphoma | [2] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 19 Inhibitor drugs | + | ||||
1 | CHR-3996 | Drug Info | [1] | |||
2 | Diaryl amine derivative 4 | Drug Info | [3] | |||
3 | PMID29671355-Compound-11 | Drug Info | [4] | |||
4 | PMID29671355-Compound-21 | Drug Info | [4] | |||
5 | PMID29671355-Compound-25 | Drug Info | [4] | |||
6 | PMID29671355-Compound-31 | Drug Info | [4] | |||
7 | PMID29671355-Compound-43 | Drug Info | [4] | |||
8 | PMID29671355-Compound-44 | Drug Info | [4] | |||
9 | PMID29671355-Compound-55 | Drug Info | [4] | |||
10 | PMID29671355-Compound-56 | Drug Info | [4] | |||
11 | PMID29671355-Compound-57 | Drug Info | [4] | |||
12 | PMID29671355-Compound-59 | Drug Info | [4] | |||
13 | PMID29671355-Compound-61 | Drug Info | [4] | |||
14 | PMID29671355-Compound-62 | Drug Info | [4] | |||
15 | PMID29671355-Compound-67 | Drug Info | [4] | |||
16 | PMID29671355-Compound-8 | Drug Info | [4] | |||
17 | PMID29671355-Compound-9 | Drug Info | [4] | |||
18 | droxinostat | Drug Info | [5] | |||
19 | RGFP966 | Drug Info | [6] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
1 | Thyroid hormone signaling pathway | |||||
2 | Alcoholism | |||||
3 | Viral carcinogenesis | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Wnt signaling pathway | |||||
PID Pathway | [+] 5 PID Pathways | + | ||||
1 | Signaling events mediated by HDAC Class II | |||||
2 | Signaling events mediated by HDAC Class I | |||||
3 | Retinoic acid receptors-mediated signaling | |||||
4 | Validated targets of C-MYC transcriptional repression | |||||
5 | Regulation of retinoblastoma protein |
References | Top | |||||
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REF 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. | |||||
REF 2 | ClinicalTrials.gov (NCT03397706) Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV-Associated Lymphoid Malignancies. U.S. National Institutes of Health. | |||||
REF 3 | Novel histone deacetylase 6 (HDAC6) selective inhibitors: a patent evaluation (WO2014181137).Expert Opin Ther Pat. 2017 Mar;27(3):229-236. | |||||
REF 4 | HDAC inhibitors: a 2013-2017 patent survey.Expert Opin Ther Pat. 2018 Apr 19:1-17. | |||||
REF 5 | Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands. Mol Cancer Ther. 2010 Jan;9(1):246-56. | |||||
REF 6 | 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. |
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