Mocetinostat (MGCD0103)

Catalog No.S1122
5 5 21 Product Citations

Mocetinostat (MGCD0103) is a potent HDAC inhibitor with most potency for HDAC1 with IC50 of 0.15 μM, 2- to 10- fold selectivity against HDAC2, 3, and 11, and no activity to HDAC4, 5, 6, 7, and 8. Phase 2.

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Mocetinostat (MGCD0103) Chemical Structure

Mocetinostat (MGCD0103) Chemical Structure
Molecular Weight: 396.44

Validation & Quality Control

Customer Reviews(6)

Quality Control & MSDS

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Product Description

Biological Activity

Description Mocetinostat (MGCD0103) is a potent HDAC inhibitor with most potency for HDAC1 with IC50 of 0.15 μM, 2- to 10- fold selectivity against HDAC2, 3, and 11, and no activity to HDAC4, 5, 6, 7, and 8. Phase 2.
Targets HDAC1 [1] HDAC2 [1] HDAC11 [1] HDAC3 [1] HDAC4 [1]

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IC50 0.15 μM 0.29 μM 0.59 μM 1.66 μM >10 μM
In vitro MGCD0103 inhibits only a subset of the nine human recombinant HDACs, including HDAC1, HDAC2, HDAC3, and HDAC11 at nanomolar or low micromolar concentrations, in a dose-dependent manner. MGCD0103 reveals most potent inhibitory activity against human HDAC1 and HDAC2 enzymes in vitro, and it does not inhibit class II HDACs. The exocyclic amino group in MGCD0103 is necessary for enzyme inhibitory activity because HDAC-inhibitory activity against HDAC1 and HDAC2 is completely abolished with the desamino analogue. The inhibitory activity of MGCD0103 reaches the maximum plateau at 6 μM, and the maximal inhibitable enzyme pool affected by MGCD0103 is 75% of the total enzyme activity in HCT116 cells whereas NVP-LAQ824 inhibits almost 100% of that in these cells. In A549 cells, MGCD0103 also exhibits dose-dependent inhibition of HDAC activity in whole cells. [1]
In vivo MGCD0103 significantly inhibites growth of human tumor xenografts in nude mice and the antitumor activity correlated with induction of histone acetylation in tumors. P.O. administration of MGCD0103 (2HBr salt) significantly decreases growth of implanted advanced A549 tumors in nude mice in a dose-dependent manner after 13 days of daily administration. MGCD0103 (170 mg/kg for 2HBr salt, corresponding to 120 mg/kg of free base) significantly blockes growth of tumors compared with vehicle treatment alone with no change in body weight. In addition, MGCD0103 does not reduce WBC counts and is well tolerated. MGCD0103 is also orally active in many other human tumor xenograft models including NSCLC H1437. MGCD0103 at 80 mg/kg (free base) almost completely blocks the growth of H1437 tumors after 13 days of daily p.o. administration with no reduction of body weight in animals. [1] MGCD0103 reduces pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. Moreover, MGCD0103 improves pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

HDAC enzyme assay in vitro The deacetylase enzyme assay is based on a homogeneous fluorescence release assay. Purified recombinant HDAC enzymes are incubated with MGCD0103 diluted in various concentrations for 10 minutes in assay buffer [25 mM HEPES (pH 8.0), 137 mM NaCl, 1 mM MgCl2, 2.7 mM KCl] at room temperature. The substrate Boc-Lys(ε-Ac)-AMC is added to the reaction for further incubation at 37 °C. The concentration of the substrate and the incubation time varies for different isotypes of HDAC enzymes. A 20-min trypsin incubation at room temperature allows the release of the fluorophore from the deacetylated substrate. The fluorescent signal is detected by fluorometer at excitation of 360 nm, emission of 470 nm, and cutoff at 435 nm.

Cell Assay: [1]

Cell lines Human mammary epithelial cells (HMEC), human foreskin fibroblasts (MRHF) cells
Concentrations 0-60 μM
Incubation Time 72 hours
Method Human mammary epithelial cells (HMEC) and human foreskin fibroblasts (MRHF) cells in 96-well plates are incubated with MGCD0103 at various concentrations for 72 hours at 37 °C in 5% CO2. MTT is added at a final concentration of 0.5 mg/ml and incubated with the cells for 4 hours before an equal volume of solubilization buffer [50% N,N-dimethylformamide, 20% SDS (pH 4.7)] is added. After overnight incubation, solubilized dye is quantified by reading at 570 nm using a reference at 630 nm. Absorbance values are converted to cell numbers according to a standard growth curve of the relevant cell line. The concentration which reduces cell numbers to 50% relative to DMSO-treated cells is determined as MTT IC5

Animal Study: [1]

Animal Models Female CD-1 nude mice bearing H1437 tumors
Formulation PBS acidified with 0.1 M HCl or PEG400/0.2 M HCl saline, 40:60
Dosages 80 mg/kg
Administration Administered via p.o.
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Fournel M, et al. Mol Cancer Ther. 2008, 7(4), 759-768.

[2] Cavasin MA, et al. Circ Res. 2012, 110(5), 739-748.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-10-24)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02236195 Recruiting Urothelial Carcinoma MethylGene Inc. October 2014 Phase 2
NCT02018926 Recruiting Myelodysplastic Syndrome MethylGene Inc. December 2013 Phase 1|Phase 2
NCT00666497 Terminated Acute Myeloid Leukemia (AML)|Myelodysplastic Syndrome (MDS) MethylGene Inc. June 2008 Phase 2
NCT00543582 Terminated Hodgkin Lymphoma|Non-Hodgkin Lymphoma (Follicular or Large Diffuse B-cell Lymphoma or Mantle Cell Lymphoma) MethylGene Inc. October 2007 Phase 2
NCT00511576 Terminated Breast Cancer|Lung Cancer|Pulmonary Cancer|Non-Small-Cell Lung Carcinoma|Prostate Cancer|Prostatic Cancer|Gastric Cancer|Stomach Cancer MethylGene Inc. August 2007 Phase 1

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Chemical Information

Download Mocetinostat (MGCD0103) SDF
Molecular Weight (MW) 396.44
Formula

C23H20N6O

CAS No. 726169-73-9
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms MG0103
Solubility (25°C) * In vitro DMSO 13 mg/mL (32 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide

Research Area

Customer Reviews (6)


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Rating
Source Oncogene 2012 32, 3896-903. Mocetinostat (MGCD0103) purchased from Selleck
Method In vitro cytotoxicity assays (MTT)
Cell Lines MCAS cell
Concentrations 0.1-100uM
Incubation Time 48 h
Results In vitro cytotoxicity assays of MCAS control and knockdown cell lines to a panel of HDAC inhibitors currently in clinical and preclinical trials showed enhanced sensitivity of the CtBP2 knockdown cell lines to most of the HDAC inhibitors compared with the control cell line. It is also noted that in the treatment with MGCD0103 and valproic acid, the differences between the control and knockdown cell lines are significant only in the very high doses.

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Rating
Source J Biol Chem 2011 286, 23842–23851. Mocetinostat (MGCD0103) purchased from Selleck
Method filipin fluorescence and quantification
Cell Lines NPC-26 mutant fibroblast line
Concentrations 5 μM
Incubation Time 18 h
Results MGCD0103 (5 μM), the HDAC class-specific inhibitors MC1568 and SAHA also reduced filipin accumulation in NPC-26 compared with untreated cells after 24 h of treatment.

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Rating
Source PLoS One 2011 6, e17138. Mocetinostat (MGCD0103) purchased from Selleck
Method Western blot, Enzymatic Assays of Class I HDACs Following Immunoprecipitation (IP), Assessment of Baseline and Drug Induced Apoptosis
Cell Lines THP-1 cells
Concentrations 0.7 μM
Incubation Time 3/24 h
Results Treatments with LBH-589, PXD101, and SAHA, but not with MGCD0103 and the other HDACIs, resulted in hyperacetylation ofa-tubulin, the substrate of HDAC6 (Figure A). IP followed by enzymatic assays revealed that both LBH-589 and PXD101 treatments resulted in the greatest inhibition of HDAC1 activities (>80% relative to control), compared to other HDACIs tested (Figure C). This was accompanied by significantly higher extents of proliferation inhibition (as reflected in percent decrease of live cells relative to untreated cells) and apoptosis (Figures E&F). Essentially the same results were obtained in THP-1 cells when the HDACI treatments were extended to 24 h, though the levels of apoptosis induced by the drugs were substantially higher (Figures B, D, E&F)

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Rating
Source PLoS One 2011 6, e17138. Mocetinostat (MGCD0103) purchased from Selleck
Method Western blot
Cell Lines THP-1 cells
Concentrations 0.7 μM
Incubation Time 3/24 h
Results Effects of MGCD0103 and other HDACIs on p21, c-Myc, and Bim expression, and in inducing DNA damage (as reflected in cH2AX) were both drug-dependent and time-dependent, as reflected in results at 3h and 24h.

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Rating
Source PLoS One 2012 7, e52095. Mocetinostat (MGCD0103) purchased from Selleck
Method Western blot
Cell Lines PANC1/AsPc-1/BxPC-3/HPDE cells
Concentrations 0.125-1uM
Incubation Time 96 h
Results Treatments of PANC-1 cells with variable concentrations of MGCD0103 (0–1.0 uM) resulted in a dose-dependent hyperacetylation of histone H4, while having no effects on alpha-tubulin (a HDAC6 substrate) acetylation or total H4 levels (Figure 2A). Treatments with MC1568 also resulted in acetylation of histone H4 (obvious at 5 and 10 uM), however, to a much lesser extent compared to MGCD0103, and the levels of acetylated histone H4 plateaued at 5 and 10 uM. Further, these treatments had no impact on alpha-tubulin acetylation.

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Rating
Source Dr. Zhang of Tianjin Medical University. Mocetinostat (MGCD0103) purchased from Selleck
Method Western blot
Cell Lines MDA-MB-231 cell line
Concentrations 0-20 μM
Incubation Time
Results MGCD0103 treatment resulted in a reduction of Histone H3 phosphorylation.

Product Citations (21)

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