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Mocetinostat (formerly MGCD-0103 or MG-0103), is a potent, benzamide-based and orally bioavailable Class I-selective inhibitor of human histone deacetylases (HDAC) with potentianl anticancer activities. Mocetinostat shows little to no inhibition against class II HDACs (HDAC4–8), but it inhibits class I HDACs like HDAC1/2/3 and class IV (like HDAC11) with IC50s of 0.15 μmol/L, 0.29 μmol/L, 1.66 μmol/L, and 0.59 μmol/L, respectively. Acute myelogenous leukemia, Hodgkin's lymphoma, and follicular lymphoma are among the cancers for which clinical trials are presently being conducted.
Physicochemical Properties
| Molecular Formula | C23H20N6O | |
| Molecular Weight | 396.44 | |
| Exact Mass | 396.169 | |
| Elemental Analysis | C, 69.68; H, 5.08; N, 21.20; O, 4.04 | |
| CAS # | 726169-73-9 | |
| Related CAS # | 726169-73-9; 944537-89-7 (HBr) | |
| PubChem CID | 9865515 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Index of Refraction | 1.730 | |
| LogP | 1.88 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 30 | |
| Complexity | 538 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | O=C(C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N([H])C1=NC([H])=C([H])C(C2=C([H])N=C([H])C([H])=C2[H])=N1)N([H])C1=C([H])C([H])=C([H])C([H])=C1N([H])[H] |
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| InChi Key | HRNLUBSXIHFDHP-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C23H20N6O/c24-19-5-1-2-6-21(19)28-22(30)17-9-7-16(8-10-17)14-27-23-26-13-11-20(29-23)18-4-3-12-25-15-18/h1-13,15H,14,24H2,(H,28,30)(H,26,27,29) | |
| Chemical Name | N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl]benzamide | |
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| 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 |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | HDAC1 ( IC50 = 0.15 μM ); HDAC2 ( IC50 = 0.29 μM ); HDAC11 ( IC50 = 0.59 μM ); HDAC3 ( IC50 = 1.66 μM ) | |
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | The homogeneous fluorescence release assay serves as the foundation for the deacetylase enzyme assay. For ten minutes, pure recombinant HDAC enzymes are incubated in assay buffer (25 mM HEPES (pH 8.0), 137 mM NaCl, 1 mM MgCl2, and 2.7 mM KCl) at room temperature with MGCD0103 diluted in different concentrations. For additional incubation at 37 °C, the substrate Boc-Lys(ε-Ac)-AMC is added to the reaction. For various isotypes of HDAC enzymes, there are differences in the substrate concentration and incubation duration. After a room temperature trypsin incubation of 20 minutes, the fluorophore can be released from the deacetylated substrate. A fluorometer is used to detect the fluorescent signal at 360 nm of excitation, 470 nm of emission, and 435 nm of cutoff. | |
| Cell Assay | Mocetinostat is added to cells in 96-well plates and incubated for 72 hours at 37°C with 5% CO2 at different concentrations. After incubating the cells for four hours at a final concentration of 0.5 mg/mL of MTT, an equal volume of solubilization buffer (50 percent N,N-dimethylformamide and 20 percent SDS, pH 4.7)) is added. The solubilized dye is measured at 570 nm using a reference at 630 nm following an overnight incubation. A standard growth curve of the relevant cell line is used to convert absorbance values to cell numbers. MTT IC50 is the concentration at which the number of cells is reduced by 50% in comparison to DMSO-treated cells.[1] | |
| Animal Protocol |
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| References |
[1]. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008 Apr;7(4):759-68. [2]. The Effect of MGCD0103 on CYP450 Isoforms Activity of Rats by Cocktail Method. Biomed Res Int. 2015;2015:517295. |
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| Additional Infomation |
Mocetinostat has been used in trials studying the treatment of Lymphoma, Urothelial Carcinoma, Relapsed and Refractory, Myelodysplastic Syndrome, and Metastatic Leiomyosarcoma, among others. Mocetinostat is a rationally designed, orally available, Class 1-selective, small molecule, 2-aminobenzamide HDAC inhibitor with potential antineoplastic activity. Mocetinostat binds to and inhibits Class 1 isoforms of HDAC, specifically HDAC 1, 2 and 3, which may result in epigenetic changes in tumor cells and so tumor cell death; although the exact mechanism has yet to be defined, tumor cell death may occur through the induction of apoptosis, differentiation, cell cycle arrest, inhibition of DNA repair, upregulation of tumor suppressors, down regulation of growth factors, oxidative stress, and autophagy, among others. Overexpression of Class I HDACs 1, 2 and 3 has been found in many tumors and has been correlated with a poor prognosis. Mechanism of Action Mocetinostat is a novel isotypic-selective inhibitor of the enzyme histone deacetylase (HDAC). HDAC inhibitors act by turning on tumour suppressor genes that have been inappropriately turned off. Tumour suppressor genes are a natural defense against cancer. It is therefore hypothesized that specifically inhibiting those HDACs involved in cancer with Mocetinostat may restore normal cell function and reduce or inhibit tumour growth. Pharmacodynamics All HDAC inhibitors induce histone H3 hyperacetylation, correlating with inhibition of proliferation, induction of cell differentiation and apoptosis. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.25 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5224 mL | 12.6122 mL | 25.2245 mL | |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 mL |