A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases.
Luo X., Liu Y., Kubicek S., Myllyharju J., Tumber A., Ng S., Che KH., Podoll J., Heightman TD., Oppermann U., Schreiber SL., Wang X.
Histone methylations are important chromatin marks that regulate gene expression, genomic stability, DNA repair, and genomic imprinting. Histone demethylases are the most recent family of histone-modifying enzymes discovered. Here, we report the characterization of a small-molecule inhibitor of Jumonji C domain-containing histone demethylases. The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain-containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.