Drug Details

General Information of the Drug (ID: DR2632)
Name
Vorinostat
Synonyms
NHNPODA; SAHA; SHH; Zolinza; Merck brand of Vorinostat; OCTANEDIOIC ACID HYDROXYAMIDE PHENYLAMIDE; SAHA cpd; Suberanilohydroxamic acid; Suberoylanilide hydroxamic acid; Vorinostat MSD; Vorinostat [USAN]; M344; MK0683; SKI390; WIN64652; MK-0683; SAHA, Suberoylanilide hydroxamic acid; SW-064652; Zolinza (TN); Vorinostat (JAN/USAN); N1-hydroxy-N8-phenyloctanediamide; Zolinza, MK-0683, SAHA; N'-hydroxy-N-phenyloctanediamide; N-Hydroxy-N'-phenyl octanediamide; N-Hyrdroxy-N'-phenyloctanediamide; N-hydroxy-N'-phenyloctanediamide; N-hydroxy-N'-phenyl-octane-1,8-diotic acid diamide; Vorinostat (HDAC inhibitor)
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Molecular Type
Small molecule
Disease Mycosis fungoides [ICD-11: 2B01] Approved [1]
Structure
Click to Download Mol
2D MOL

3D MOL

ADMET Property
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability
Clearance
The drug present in the plasma can be removed from the body at the rate of 28 mL/min/kg
Half-life
The concentration or amount of drug in body reduced by one-half in 2 hours
Metabolism
The drug is metabolized via beta-oxidation
Unbound Fraction
The unbound fraction of drug in plasma is 0.29%
Vd
Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.5 L/kg
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    Click to Show/Hide the Molecular Information and External Link(s) of This Natural Product
Formula
C14H20N2O3
PubChem CID
5311
Canonical SMILES
C1=CC=C(C=C1)NC(=O)CCCCCCC(=O)NO
InChI
1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18)
InChIKey
WAEXFXRVDQXREF-UHFFFAOYSA-N
CAS Number
CAS 149647-78-9
GDSC
Vorinostat
TTD Drug ID
D0E7PQ
DrugBank ID
DB02546
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Arsenic trioxide      Realgar and orpiment     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression CDKN1A  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
                    In-vivo Model Male Balb/c nude mice at 4-6 weeks of age were injected sc in the hind limb with 1 * 107 H1299 cells in 100 ul of phosphate-buffered saline.
                    Experimental
                    Result(s)		 Combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model.
          Bufalin      Bufo gargarizans     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Activity AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
                    In-vitro Model MDA-MB-231 CVCL_0062 Breast adenocarcinoma Homo sapiens
A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors.
          Celastrol      Celastrus strigillosus     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression CDH1  Molecule Info 
Pathway MAP
Up-regulation Expression p105  Molecule Info 
Pathway MAP
                    In-vitro Model PLA-801D CVCL_7110 Lung giant cell carcinoma Homo sapiens
                    In-vivo Model Human lung cancer xenografts were established by subcutaneously inoculating 5*106 95-D cells into nude mice.
                    Experimental
                    Result(s)		 The synergistic anticancer effects of celastrol and SAHA was demonstrated due to their reciprocal sensitisation, which was simultaneously regulated by NF-kappaB and E-cadherin.
          Cladribine      Homo sapiens     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model J45.01 CVCL_2530 T acute lymphoblastic leukemia Homo sapiens
U-937 CVCL_0007 Adult acute monocytic leukemia Homo sapiens
                    Experimental
                    Result(s)		 The Clad+Gem+Bu+SAHA combination provides synergistic cytotoxicity in lymphoma cell lines.
          Epigallocatechin gallate      Hamamelis virginiana     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Activity CASP3  Molecule Info 
Pathway MAP
Up-regulation Activity CASP7  Molecule Info 
Pathway MAP
Up-regulation Activity CASP9  Molecule Info 
Pathway MAP
Down-regulation Expression CCNA1  Molecule Info 
Pathway MAP
Down-regulation Expression CDK2  Molecule Info 
Pathway MAP
Down-regulation Expression CDK4  Molecule Info 
Pathway MAP
Up-regulation Expression CDKN1A  Molecule Info 
Pathway MAP
Down-regulation Expression p105  Molecule Info 
Pathway MAP
                    In-vitro Model A-375 CVCL_0132 Amelanotic melanoma Homo sapiens
Hs 294T CVCL_0331 Melanoma Homo sapiens
G-361 CVCL_1220 Melanoma Homo sapiens
                    Experimental
                    Result(s)		 The combination treatment resulted in significantly greater inhibition of cell proliferation, increased apoptosis, activation of p21, p27 and caspases (3, 7 and 9) and Bax as well as down-regulation of cdk2, cdk4, cyclin A, NF-kappaB protein p65/RelA and Bcl2 protein and transcript.
          Flavopiridol      Dysoxylum binectariferum     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression CCNB1  Molecule Info 
Pathway MAP
Down-regulation Expression MAD2L1  Molecule Info 
Pathway MAP
Down-regulation Expression MMP-2  Molecule Info 
Pathway MAP
                    In-vitro Model CHLA-15 CVCL_6594 Neuroblastoma Homo sapiens
CHLA-20 CVCL_6602 Neuroblastoma Homo sapiens
SK-N-BE(1) CVCL_9898 Neuroblastoma Homo sapiens
SK-N-RA CVCL_AQ53 Neuroblastoma Homo sapiens
LA-N-6 CVCL_1363 Neuroblastoma Homo sapiens
CHLA-136 CVCL_6590 Neuroblastoma Homo sapiens
CHLA-79 CVCL_6608 Neuroblastoma Homo sapiens
CHLA-119 CVCL_A055 Neuroblastoma Homo sapiens
CHLA-90 CVCL_6610 Neuroblastoma Homo sapiens
CHLA-172 CVCL_A056 Neuroblastoma Homo sapiens
                    Experimental
                    Result(s)		 Combination of vorinostat and flavopiridol is selectively cytotoxic to multidrug-resistant neuroblastoma cell lines with mutant TP53. The combination caused reduction in the expression of G(2)/M proteins (cyclin B1, Mad2, MPM2) in 2 cell lines with mt TP53 but not in those with wt TP53.
          Mithramycin A      Streptomyces tanashiensis     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model Primary tumor cells derived from Sezary syndrome patients Sezary syndrome Homo sapiens
                    Experimental
                    Result(s)		 MTR, like SAHA, induced the apoptosis of SS cells, while the two drugs in combination showed clear synergy or potentiation.
          Pterostilbene      Vitis vinifera     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression HIF-1A  Molecule Info 
Pathway MAP
Down-regulation Expression IL1B  Molecule Info 
Pathway MAP
Down-regulation Expression MTA1  Molecule Info 
Pathway MAP
Down-regulation Expression VEGFA  Molecule Info 
Pathway MAP
                    In-vitro Model LNCaP CVCL_0395 Prostate carcinoma Homo sapiens
                    In-vivo Model Female C57BL/6J mouse homozygous with "floxed" allele of Pten gene were used in this study.
                    Experimental
                    Result(s)		 Pterostilbene sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1Alpha, VEGF, and IL-1Beta leading to decreased angiogenesis.
          Silibinin      Carduus marianus     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [10]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-xL  Molecule Info 
Pathway MAP
Down-regulation Expression BIRC5  Molecule Info 
Pathway MAP
Down-regulation Expression CCNB1  Molecule Info 
Pathway MAP
Up-regulation Expression CDKN1A  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
Down-regulation Expression POLD1  Molecule Info 
Pathway MAP
Down-regulation Expression XIAP  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction Cell cycle arrest in G2/M phase
                    In-vitro Model NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H358 CVCL_1559 Lung adenocarcinoma Homo sapiens
NCI-H322 CVCL_1556 Lung adenocarcinoma Homo sapiens
                    In-vivo Model Six week old athymic (nu/nu) male nude mice were subcutaneously injected with three million exponentially growing H1299 cells mixed with equal volume (1:1) of matrigel on the right flank of each mouse.
                    Experimental
                    Result(s)		 Combinations of SAHA with silibinin synergistically augmented the cytotoxic effects of the single agent, which was associated with a dramatic increase in p21 (Cdkn1a).
          Vincristine      Catharanthus roseus     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-xL  Molecule Info 
Pathway MAP
Up-regulation Expression CASP3  Molecule Info 
Pathway MAP
Down-regulation Expression HDAC6  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
Up-regulation Expression PARP1  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction Cell cycle arrest in G2/M phase
                    In-vitro Model MOLT-4 CVCL_0013 Adult T acute lymphoblastic leukemia Homo sapiens
CCRF-CEM CVCL_0207 T acute lymphoblastic leukemia Homo sapiens
                    In-vivo Model MOLT-4 cells were implanted (1*107 cells/ml) into severe combined immunodeficiency (SCID) mice.
                    Experimental
                    Result(s)		 The combination of vincristine and SAHA on T cell leukemic cells resulted in a change in microtubule dynamics contributing to M phase arrest followed by induction of the apoptotic pathway.
Target and Pathway
Target(s) Histone deacetylase 1 (HDAC1)  Molecule Info  [12]
KEGG Pathway Cell cycle Click to Show/Hide
2 Notch signaling pathway
3 Thyroid hormone signaling pathway
4 Huntington's disease
5 Amphetamine addiction
6 Alcoholism
7 Epstein-Barr virus infection
8 Pathways in cancer
9 Transcriptional misregulation in cancer
10 Viral carcinogenesis
11 MicroRNAs in cancer
12 Chronic myeloid leukemia
NetPath Pathway TCR Signaling Pathway Click to Show/Hide
Panther Pathway Wnt signaling pathway Click to Show/Hide
2 p53 pathway
Pathway Interaction Database Regulation of nuclear SMAD2/3 signaling Click to Show/Hide
2 Notch signaling pathway
3 E2F transcription factor network
4 Presenilin action in Notch and Wnt signaling
5 Signaling events mediated by HDAC Class I
6 Regulation of Telomerase
7 Glucocorticoid receptor regulatory network
8 Sumoylation by RanBP2 regulates transcriptional repression
9 Regulation of Androgen receptor activity
10 IL3-mediated signaling events
11 Validated nuclear estrogen receptor alpha network
12 Retinoic acid receptors-mediated signaling
13 Hedgehog signaling events mediated by Gli proteins
14 Regulation of nuclear beta catenin signaling and target gene transcription
15 Validated targets of C-MYC transcriptional repression
16 Regulation of retinoblastoma protein
17 Notch-mediated HES/HEY network
Reactome G0 and Early G1 Click to Show/Hide
2 p75NTR negatively regulates cell cycle via SC1
3 Formation of the beta-catenin:TCF transactivating complex
4 NOTCH1 Intracellular Domain Regulates Transcription
5 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
6 Constitutive Signaling by NOTCH1 PEST Domain Mutants
7 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
8 HDACs deacetylate histones
9 Deactivation of the beta-catenin transactivating complex
10 NoRC negatively regulates rRNA expression
11 RNA Polymerase I Transcription Initiation
12 Factors involved in megakaryocyte development and platelet production
WikiPathways SIDS Susceptibility Pathways Click to Show/Hide
2 Notch Signaling Pathway
3 TGF beta Signaling Pathway
4 IL-6 signaling pathway
5 Apoptosis-related network due to altered Notch3 in ovarian cancer
6 Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
7 Notch Signaling Pathway
8 Retinoblastoma (RB) in Cancer
9 Neural Crest Differentiation
10 TWEAK Signaling Pathway
11 Integrated Breast Cancer Pathway
12 Signalling by NGF
13 RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription
14 Mitotic G1-G1/S phases
15 Factors involved in megakaryocyte development and platelet production
16 Cell Cycle
17 Androgen receptor signaling pathway
References
Reference 1 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. (Ligand id: 6852).
Reference 2 Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide. Toxicol Appl Pharmacol. 2011 Nov 15;257(1):59-66.
Reference 3 Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors. Biochem Biophys Res Commun. 2016 Sep 9;478(1):227-233.
Reference 4 Simultaneous NF-kappaB inhibition and E-cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo. Int J Cancer. 2014 Oct 1;135(7):1721-32.
Reference 5 Cladribine, gemcitabine, busulfan, and SAHA combination as a potential pretransplant conditioning regimen for lymphomas: A preclinical study. Exp Hematol. 2016 Jun;44(6):458-65.
Reference 6 Anti-melanoma effects of vorinostat in combination with polyphenolic antioxidant (-)-epigallocatechin-3-gallate (EGCG). Pharm Res. 2010 Jun;27(6):1103-14.
Reference 7 Combination of vorinostat and flavopiridol is selectively cytotoxic to multidrug-resistant neuroblastoma cell lines with mutant TP53. Mol Cancer Ther. 2010 Dec;9(12):3289-301.
Reference 8 Vorinostat and Mithramycin A in combination therapy as an interesting strategy for the treatment of Sezary T lymphoma: a transcriptomic approach. Arch Dermatol Res. 2017 Oct;309(8):611-623.
Reference 9 Targeting MTA1/HIF-1Alpha signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression. Cancer Med. 2017 Nov;6(11):2673-2685.
Reference 10 Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics. 2012 Oct;7(10):1161-72.
Reference 11 The synergic effect of vincristine and vorinostat in leukemia in vitro and in vivo. J Hematol Oncol. 2015 Jul 10;8:82.
Reference 12 Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov. 2009 Sep;8(9):724-32.
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