CoREST in Peace: Dual Action Inhibitors of Histone Deacetylase and Lysine Specific Demethylase

Abstract

Histone deacetylases (HDACs) have been shown to act broadly on thousands of protein lysine acetylation sites to regulate cell growth and gene expression. The class I enzymes HDAC1 and HDAC2 can be found in various corepressor complexes in cells, including the CoREST complex, that also incorporates histone demethylase LSD1. Various combinations of HDAC inhibitors and LSD1 inhibitors have been reported previously to show additive or synergistic effects as anti‐tumor agents. In this study, we prepared several dual action HDAC/LSD1 inhibitors that integrate established pharmacophores targeting the active sites of these enzymes. We showed that several of these hybrid compounds can potently inhibit HDAC and LSD1 activity while maintaining the selectivity associated with the parent molecules. One of these compounds, 2‐68, derived from HDAC inhibitor MS‐275 (entinostat) and LSD1 inhibitor bizine, induced potent and predicted increases in histone H3 K9 acetylation and H3 K4 methylation. Interestingly, MS‐275 and 2‐68 showed anti‐proliferative effects across a panel of melanoma lines, but 2‐68 did not inhibit the proliferation of primary human melanocytes whereas MS‐275 did. Furthermore, we showed that, compared to the parent compounds, 2‐68 was superior in suppressing the function of regulatory T cells, suggesting that dual action CoREST inhibitors may offer advantages in enhancing tumor immune surveillance.