Targets And Preclinical Rationale
Mocetinostat is a potent, selective inhibitor of class I histone deacetylases (HDACs). HDAC is a family of 11 enzymes (isoforms) that may act as master regulators of gene expression. We have determined that class I HDAC isoforms are involved in cancer and have developed proprietary tools and know-how to design isoform-selective inhibitors such as Mocetinostat against these targets.
Inhibition of these cancer-related isoforms results in multiple and desirable anti-cancer effects such as (i) the inhibition of cancer cell proliferation, (ii) the induction of apoptosis (cell death) of cancer cells, (iii) cell cycle regulation, (iv) the induction of tumor suppressor genes, and (v) the blocking of tumor angiogenesis (development of new tumor blood vessels).
In intact cells, Mocetinostat inhibited only a fraction of the total HDAC activity (due to its selectivity) and showed long-lasting inhibitory activity even upon drug removal. Mocetinostat induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. Mocetinostat 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, Mocetinostat significantly inhibited growth of a wide variety of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. This antitumor activity exceeded the activity from competitor molecules, while there was less overall toxicity, such as less myelosuppression and weight loss.