 The post-translation modifications of histones play a crucial role in the regulation of gene architecture and expression. Of particular importance is aberrant methylation at specific histone lysine residues, which is associated with the silencing of tumor suppressor genes. The recently discovered enzyme lysine-specific demethylase 1 (LSD1) catalyzes the oxidative demethylation of histone 3 methyllysine 4 (H3K4me1) and histone 3 dimethyllysine 4 (H3K4me2), and is a validated target for antitumor drug discovery. As part of a program aimed at the design, synthesis and evaluation of specific histone demethylase inhibitors, we recently disclosed potent (bis)urea and (bis)thiourea LSD1 inhibitors (Sharma et al., J. Med. Chem. 2010, 53, 5197�5212) that increase levels of H3K4me and H3K4me2 and promote re-expression of aberrantly silenced genes in vitro, and suppress tumor growth in vivo (Figure 1).  Herein we report additional novel LSD1 inhibitors, as well as their in vitro and in vivo antitumor effects

Design, synthesis, and testing of novel histone demethylase inhibitors as epigenetic modulators

243rd National Meeting (2012)

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