MGCD0103, also known as Mocetinostat, is a rationally designed, orally available, Class 1-selective, small molecule, 2-aminobenzamide HDAC inhibitor with potential antineoplastic activity. MGCD0103 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.
CAS Number: 726169-73-9
Molecular Weight: 396.44
Chemical Name: N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: DMSO: 13 mg/mL(32.79 mM).
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
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.
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. 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.
- Cavasin MA, et al. Circ Res. 2012, 110(5), 739-748.
- Fournel M, et al. Mol Cancer Ther. 2008, 7(4), 759-768.
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