Enhanced Isotype-Selectivity and Antiproliferative Activity of Thiophenyl Derivatives of Benzamide HDAC Inhibitors In Human Cancer Cells

4725 Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy in recent years. Currently several HDAC pan-inhibitors are in clinical trials, such as SAHA. We hypothesized that isotype-specific HDAC inhibitors will exhibit significant antitumor activity but have less side effects as human cancer therapeutic agents. As our initial effort, we designed and synthesized the isotype-selective HDAC inhibitor MGCD0103 which targets to HDAC1, 2, 3 and 11 and in vitro and exhibits significant antitumor activity in vivo . In order to further understand the isotype-specific role of HDAC enzymes, especially class I HDAC enzymes, in human cancers, we designed a class of thiophenyl substituted benzamides as novel HDAC inhibitors. In this poster, as a typical example of compounds resulting from this approach, we describe the biological assessment of the thiophenyl derivative of CI-994 (Compound 1) both in vitro and in vivo . We demonstrate that thiophenyl modification of CI-994 significantly enhanced HDAC inhibitory activity against its target HDAC enzymes and changes its selectivity profiles both in vitro and in cancer cells. Consistent with its enzyme inhibitory potency in vitro , antiproliferative activity of Compound 1 is much more potent than its parental CI-994 in various cancer cell lines in vitro . Compound 1 also exhibits antitumor activity in xenograft models in mice in vivo . Selective inhibition of HDAC enzymes by thiophenyl-substituted benzamides may be a novel approach to identify anti-cancer agents.