Vorinostat (SAHA; MK0683)

Alias: MK0683; SAHA; M344; CCRIS 8456; CCRIS8456; CCRIS-8456; HSDB 7930; Vorinostat; suberoylanilide hydroxamic acid; MK-0683; MK 0683; MK0683; M344; HSDB 7930; Trade name: Zolinza
Cat No.:V0255 Purity: ≥98%
Vorinostat (formerly known as suberanilohydroxamic acid, MK-0683;CCRIS-8456; HSDB 7930; SAHA; trade name: Zolinza) is a potent,orally bioavailableand non-selective pan-inhibitor of histone deacetylases (HDACs) with antitumor activity.
Vorinostat (SAHA; MK0683) Chemical Structure CAS No.: 149647-78-9
Product category: HDAC
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

In a test without cells, it inhibits HDACs (pooled HDACs with all isoforms) with an IC50 of less than 10 nM. With ID50 values of 10 nM and 20 nM for HDAC1 and HDAC3, respectively, it inhibits HDAC1, HDAC2, and HDAC3 (Class I), HDAC7 (Class II), and HDAC11 (Class IV). It has been demonstrated that vorinostat binds to the histone deacetylases' active site and functions as a chelator for the zinc ions that are likewise present there. Because vorinostat inhibits histone deacetylases, acetylated proteins and histones accumulate, which is essential for cell differentiation. The FDA approved SAHA, also known as Vorinostat, in October 2006, making it the first HDAC inhibitor to treat rare cutaneous T-cell lymphoma.

Biological Activity I Assay Protocols (From Reference)
Targets
HDAC1 ( IC50 = 10 nM ); HDAC3 ( IC50 = 20 nM ); HDAC2; HDAC7; HDAC11; Autophagy; Mitophagy
ln Vitro

In vitro activity: Vorinostat suppresses the activity of HDAC1 and HDAC3 with IC50 of 10 nM and 20 nM, respectively. Additionally, Vorinostat causes histone H4 to be significantly hyperacetylated. In three prostate cancer cell lines—LNCaP, PC-3, and TSU-Pr1—vorinostat inhibits growth at micromolar concentrations (2.5–7.5 μM) and causes dose-dependent cell death in LNCaP cells. [2] Treatment with vorinostat at an IC50 of 0.75 μM diminishes cell division in MCF-7 cells, causing a build-up of cells in the G1 and G2-M phases of proliferation. Vorinostat also causes the retinoblastoma-negative cell line MDA-468 and the estrogen receptor-negative cell line SKBr-3 to differentiate.[3] It takes at least eight hours of vorinostat treatment at 1 μM to permanently cause human multiple myeloma (MM) cells to undergo apoptosis. The coordinated transcriptional changes of specific functional groups of genes, such as cytokine-induced proliferative/survival signaling cascades, oncogenes-tumor suppressor genes, regulators of apoptosis, DNA synthesis-repair and cell cycle, and proteasome-ubiquitin function, characterize the gene expression profiles of Vorinostat-treated MM cells rather than a widespread transcriptional activation.[4]

ln Vivo
In comparison to control, the administration of Vorinostat (~100 mg/kg/day) significantly inhibits the growth of CWR22 human prostate xenografts in nude mice, resulting in tumor reductions of 78%, 97%, and 97% at doses of 25 mg/kg/day, 50 mg/kg/day, and 100 mg/kg/day, respectively. Vorinostat causes CWR22 cells to express prostate-specific antigen mRNA and accumulate acetylated core histones, which raises serum prostate-specific antigen levels above those estimated by tumor volume alone. [/2] By increasing histone acetylation in the brain and bridging the blood-brain barrier, oral administration of Vorinostat (0.67g/L) significantly ameliorates the motor impairment in the R6/2 mice model of Huntington's disease.[5]
Enzyme Assay
The Jurkat cell lysate is treated with ice for an hour before being centrifuged at 12,000 g for ten minutes at 4 °C to remove any remaining material. 30 μL of 50% protein G-Sepharose slurry is added to supernatants and left for an hour at 4 °C to preclearase them. Using either the homologous or heterologous immunizing peptide, beads are pelleted by centrifugation, and the supernatants are then incubated for 1 hour at 4 °C with 10 μg of IgG fraction from anti-HDAC1 or HDAC3 polyclonal antisera (preincubated for 2 hours at room temperature). Rabbits are used to raise both antisera against the carboxylterminal peptide of HDAC1 and HDAC3, using synthetic peptides coupled to keyhole limpet hemocyanin). Half an hour is spent at 4°C with 30 μL of a 50% protein G-Sepharose slurry added. After centrifuging the immune complexes, 1 mL of lysis buffer is used to wash them three times. A 3H-acetylated peptide that corresponds to amino acids 1 through 24 of histone H4 is used in the HDAC assay, and beads are resuspended in 200 μL of HDAC buffer (20 mM Tris-HCl, pH 8.0/150 mM NaCl/10% glycerol). By using scintillation counting, released [3H]acetic acid is measured. Vorinostat at varying concentrations is preincubated with the immunoprecipitated complexes for 30 minutes at 4 °C in order to conduct inhibitions studies.
Cell Assay
RIPA buffer (25 mM Tris-HCl pH 7.6, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) is used to prepare cell lysates, and the Bio-Rad DC Protein Assay is used to measure the protein concentration. Protein lysates are moved to nitrocellulose membrane after being separated via SDS-PAGE. The subsequent dilutions and antibodies are utilized: mouse anti-p21WAF1 (0.5 μg/mL), rabbit anti-HDAC1 (1 μg/mL), rabbit anti-HDAC2 (1 μg/mL), rabbit anti-HDAC3 (9 μg/mL), and rabbit anti-HDAC7 (3 μg/mL). The swine anti-rabbit and rabbit anti-mouse HRP-coupled antibodies were used as secondary antibodies, with a final concentration of 1 μg/mL. All primary antibodies are incubated at 4°C for an entire night before being washed and secondary antibodies are incubated at room temperature for two hours. The enhanced chemiluminescence assay allows for the visualization of particular protein bands. In order to exhibit uniform loading of protein samples, β-tubulin is probed on every western blot.
Animal Protocol
Isofluran is used to induce sedation in 14 male mice aged 12 weeks, after which 5×106 MES-SA cells are subcutaneously injected into the right flank of the mouse. A control group of mice is given a placebo consisting of 300 μL of empty HOP-β-CD (2-hydroxypropyl-β-cyclodextrin) vesicles. Vorinostat diluted in HOP-β-CD is given to a different group of mice daily at a dose of 50 mg/kg. Starting on the fourth day following the injection of MES-SA tumor cells, both empty vesicles and vorinostat are given intraperitoneally. Tumor size (w2 × l × 0.52; determined by caliper) and mice body weight are estimated twice a week. After receiving treatment for 21 days, the mice are all sacrificed by cervical dislocation. Different tumor parameters are determined and each tumor is isolated as a whole. Tumor slices are then formalin fixed (4%) and cryopreserved for additional analysis.
References

[1]. Proc Natl Acad Sci U S A . 1998 Mar 17;95(6):3003-7.

[2]. Cancer Res . 2000 Sep 15;60(18):5165-70.

[3]. Cancer Res . 2001 Dec 1;61(23):8492-7.

[4]. Proc Natl Acad Sci U S A . 2003 Feb 18;100(4):2041-6.

[5]. Proc Natl Acad Sci U S A . 2004 Jan 13;101(2):540-5.

[6]. Clin Cancer Res . 2004 Jun 1;10(11):3839-52.

[7]. Clin Cancer Res . 2008 Sep 1;14(17):5385-99.

[9]. Blood . 2008 Aug 1;112(3):793-804.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C14H20N2O3
Molecular Weight
264.3
Exact Mass
264.15
Elemental Analysis
C, 63.62; H, 7.63; N, 10.60; O, 18.16
CAS #
149647-78-9
Appearance
White to off-white solid powder
SMILES
C1=CC=C(C=C1)NC(=O)CCCCCCC(=O)NO
InChi Key
WAEXFXRVDQXREF-UHFFFAOYSA-N
InChi Code
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)
Chemical Name
N'-hydroxy-N-phenyloctanediamide
Synonyms
MK0683; SAHA; M344; CCRIS 8456; CCRIS8456; CCRIS-8456; HSDB 7930; Vorinostat; suberoylanilide hydroxamic acid; MK-0683; MK 0683; MK0683; M344; HSDB 7930; Trade name: Zolinza
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~53 mg/mL (~200.5 mM)
Water: <1 mg/mL
Ethanol: ~3 mg/mL (~11.4 mM)
Solubility (In Vivo)
2% DMSO+30% PEG 300+ddH2O: 5mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 3.7836 mL 18.9179 mL 37.8358 mL
5 mM 0.7567 mL 3.7836 mL 7.5672 mL
10 mM 0.3784 mL 1.8918 mL 3.7836 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01236560 Active
Recruiting
Drug: Vorinostat
Drug: Temozolomide
Brain Stem Glioma
Cerebral Astrocytoma
National Cancer Institute
(NCI)
November 15, 2010 Phase 2
Phase 3
NCT01281176 Active
Recruiting
Drug: Vorinostat
Drug: Carboplatin
Adult Solid Neoplasm National Cancer Institute
(NCI)
February 9, 2011 Phase 1
NCT02638090 Active
Recruiting
Drug: Vorinostat
Drug: Pembrolizumab
Non-small Cell Lung Cancer
Lung Cancer
H. Lee Moffitt Cancer Center
and Research Institute
March 22, 2016 Phase 1
Phase 2
NCT00268385 Active
Recruiting
Drug: Vorinostat
Drug: Temozolomide
Adult Glioblastoma
Adult Gliosarcoma
National Cancer Institute
(NCI)
December 16, 2005 Phase 1
NCT02737046 Active
Recruiting
Drug: Vorinostat
Drug: Sargramostim
Neuroblastoma New Approaches to Neuroblastoma
Therapy Consortium
September 12, 2018 Phase 1
Biological Data
  • Vorinostat (SAHA, MK0683)

    Vorinostat (SAHA, MK0683)

  • Vorinostat (SAHA, MK0683)

    Effects of SAHA on regulators of apoptosis and sensitivity to caspase-dependent drug-induced apoptosis.Proc Natl Acad Sci U S A.2004 Jan 13;101(2):540-5.



    Vorinostat (SAHA, MK0683)

  • Vorinostat (SAHA, MK0683)

    Functional impact of SAHA on the ubiquitin/proteasome pathway.Proc Natl Acad Sci U S A.2004 Jan 13;101(2):540-5.
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