Data from MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity <i>in vitro</i> and <i>in vivo</i>

Abstract

<div>Abstract<p>Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice <i>in vivo</i>, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 <i>in vitro</i>. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines <i>in vitro</i>, and HDAC inhibitory activity was required for these effects. <i>In vivo</i>, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity <i>in vivo</i> and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759–68]</p></div>