An inhibitor of histone demethylases specifically blocks cancer growth in vitro and in vivo

Abstract

Histone modifying enzymes are highly deregulated in cancers, leading to aberrant transcriptional programs and thus constitute key therapeutic targets. Using an unbiased cell‐based screen, we have identified a novel compound that modulates the activity of Jumonji histone demethylases. Here, we report the anti‐cancer properties and the mode of action of this small molecule called Elizib. We show, through viability measurements across a large panel of human cancer and normal epithelial cells, that this drug has remarkable specificity for cancer with IC50 values as low as 2 nM. In vivo, it effectively reduces tumor burden in mouse xenograft models. Elizib causes cancer‐cell specific changes in cell cycle progression, upregulates pro‐apoptotic and differentiation genes and downregulates proliferative genes, partially re‐establishing a normal transcriptional program in cancer cells, leading to their demise. Enzyme activity assays and chromatin immunoprecipitation studies demonstrate that our small molecule exerts these activities in cell culture and in vivo at least in part through inhibition of demethylases of the Jumonji family. Thus, we have identified a novel epigenetic inhibitor with specific anti‐cancer activity in cells and in vivo. Elizib opens up a new therapeutic venue and is a novel chemical tool to unravel aspects of epigenetic transcriptional regulation in cancer.