Mocetinostat (MGCD0103, MG0103)

Mocetinostat, also known as MGCD0103 or MG0103, is an isotype-selective inhibitor of human histone deacetylases (HDAC), a family of enzymes involved in epigenetic regulation of gene transcription as well as cell proliferation, death and motility. Mocetinostat potently inhibits HDAC class I (HDAC1, HDAC2, and HDAC3) and class IV (HDAC11), with values of inhibition constant IC50 of 0.15 μmol/L, 0.29 μmol/L, 1.66 μmol/L, and 0.59 μmol/L respectively, rather than HDAC class II. Mocetinostat exerts anti-tumor activity against a broad range of human cancer cells through HDAC inhibition, in which it induces histone hyperacetylation and apoptosis and causes cell cycle blockade in a dose-dependent manner.

Reference

Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, Liu J, Lu AH, Zhou NZ, Robert MF, Gillespie J, Wang JJ, Ste-Croix H, Rahil J, Lefebvre S, Moradei O, Delorme D, Macleod AR, Besterman JM, Li Z. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008; 7(4): 759-768

Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor.[Pubmed:21554162]

Expert Opin Investig Drugs. 2011 Jun;20(6):823-9.

INTRODUCTION: HDAC inhibitors (HDACIs) have the potential to restore gene expression and display antitumor effects in vitro. As single agents, HDACIs have clinical activity in lymphoma. In myeloid leukemias, combinations of DNA methylation inhibitors and HDACIs are promising. Other combinations are being studied in solid tumors. AREAS COVERED: This article covers basic information and an update on preclinical and clinical experience with the oral isotype-selective HDACI MGCD0103 (mocetinostat) in hematological malignancies and solid tumors. It also examines data concerning MGCD0103 from recent conferences and articles through to November 2010, including new data regarding responses in lymphoma and toxicities. EXPERT OPINION: MGCD0103 is well-tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules. In 2008, new patient enrollment in trials was temporarily suspended due to potential cardiac complications. This restriction was lifted in 2009 as no correlation between MGCD0103 exposure and pericardial effusions was found. New patient enrollment in MGCD0103 clinical trials requires the exclusion of patients diagnosed with significant cardiac abnormalities prior to enrollment. Clinical and pharmacodynamic data support a three-times-weekly administration at a 90 mg fixed dose. MGCD0103 displays promising antitumor activity in several hematological diseases.

Liquid chromatography mass spectrometry determination of mocetinostat (MGCD0103) in rat plasma and its application to a pharmacokinetic study.[Pubmed:24588344]

Xenobiotica. 2014 Sep;44(9):849-54.

Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including Hodgkin's lymphoma, follicular lymphoma and acute myelogenous leukemia. A sensitive and selective liquid chromatography mass spectrometry method for determination of MGCD0103 in rat plasma was developed. After addition of midazolam as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation. Chromatographic separation was achieved on a C18 (2.1 mmx50 mm, 3.5 microm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 397 for MGCD0103 and m/z 326 for the IS. Calibration plots were linear over the range of 5-5000 ng/mL for MGCD0103 in rat plasma. Mean recoveries of MGCD0103 in rat plasma were in the range of 89.7-96.1%. RSD of intra-day and inter-day precision were both<11%. The accuracy of the method ranged from 96.5% to 109.7%. The matrix effects for MGCD0103 were between 94.5% and 97.4%. The method was successfully applied to pharmacokinetic study of MGCD0103 after oral (15 mg/kg) and intravenous (3 mg/kg) administration in rats. The bioavailability of MGCD0103 was 29.3% in rats.

Metabolic changes in rats after intragastric administration of MGCD0103 (Mocetinostat), a HDAC class I inhibitor.[Pubmed:26464683]

Int J Clin Exp Pathol. 2015 Aug 1;8(8):9320-5. eCollection 2015.

MGCD0103, an isotype-selective HDACi, has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In this study, we developed a serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of intragastric administration of MGCD0103 on rats. The MGCD0103 group rats were given 20, 40, 80 mg/kg of MGCD0103 by intragastric administration each day for 7 days. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of MGCD0103 induced metabolic perturbations. As compared to the control group, the levels of L-alanine, L-isoleucine, and L-leucine of MGCD0103 group decreased. The results indicate that metabolomic methods based on GC-MS may be useful to elucidate side effect of MGCD0103 through the exploration of biomarkers (L-alanine, L-isoleucine, and L-leucine). According to the pathological changes of liver at difference dosage, MGCD0103 is hepatotoxic and its toxity is dose-dependent.

Mocetinostat (MGCD0103) is a potent, orally active and isotype-selective HDAC (Class I/IV) inhibitor with IC50s of 0.15, 0.29, 1.66 and 0.59 μM for HDAC1, HDAC2, HDAC3 and HDAC11, respectively. Mocetinostat shows no inhibition on HDAC4, HDAC5, HDAC6, HDAC7, or HDAC8.

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