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Research Articles: Therapeutics, Targets, and Development

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

Departments of ¹ Molecular Biology, ² Lead Discovery, ³ Medicinal Chemistry, ⁴ Cell Biology and Pharmacology, and ⁵ Pharmacokinetics, MethylGene, Inc., St. Laurent, Quebec, Canada

Requests for reprints: Zuomei Li, Department of Molecular Biology, MethylGene, Inc., 7220 Frederick-Banting, Montreal, Quebec H4S 2A1, Canada. Phone: 514-337-3333, ext. 245; Fax: 514-337-0550. E-mail: liz{at}methylgene.com

Abstract

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, 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 in vitro. 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 in vitro, and HDAC inhibitory activity was required for these effects. In vivo, 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 in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759–68]

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Note: M. Fournel and C. Bonfils contributed equally to this paper.

Current address for D. Delorme: Neurochem, Inc., 275 Armand-Frappier Boulevard, Laval, Quebec H7V 4A7, Canada.

Current address for A.R. MacLeod: Takeda San Diego, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.

⁶ Bonfils C., Kalita A., Dubay M., Siu L., Carducci M.A., Reid G., Martell R., Besterman J.M., Li Z. Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human, using a novel HDAC enzyme assay. Clin Cancer Res (in press).

Received 8/30/07; revised 12/20/07; accepted 1/21/08.