Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor

Abstract

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.

A Phase II Exploratory Study of PXD-101 (Belinostat) Followed by Zevalin in Patients with Relapsed Aggressive High-Risk Lymphoma

“…A phase II trial of vorinostat in 18 patients with R/R DLBCL showed 1 CR lasting over 15 months, with time to response of 2.8 months, and 1 stable disease lasting 9.9 months [16] . Mocetinostat was associated with 1 CR and 5 PR in a 41-patient cohort of a phase II trial [17] . These observations suggest a subset of patients may experience significant benefit from HDAC inhibition.…”

Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors

“…This moderate selectivity of both entinostat and tacedinaline for HDAC8 was not well reproduced in our study; therefore, the binding affinities of these inhibitors for HDAC8 presented in Table 3 should be considered with caution. Mocetinostat is 2-to 10-fold more selective for HDAC1 than HDACs 2, 3, and 11 (Boumber et al, 2011). These known selective inhibitors were used as reference compounds to guide the selection of our potent and selective inhibitors.…”

Progress and challenges in the use of latent HIV-1 reactivating agents

“…Entinostat mainly targets HDACis (HDAC 1, 2, 3), which are the HDACs most associated with HIV regulation. Mocetinostat also targets HADC 1 and is currently undergoing clinical trials for Hodgkin lymphoma [47] . Entinostat exhibits its highest potency against HDAC 1 (nanomolar range) and is less potent against HDACs 2 and 3 (micromolar range).…”