Specific Inhibitors of Histone Demethylases: Novel Chemical Agents for Breast Cancer Therapy.

摘要

Histone demethylases are a newly discovered class of non-heme iron enzymes that play an important role in regulating transcription and epigenetic inheritance. We have successfully expressed and purified highly active histone demethylases (HDMs), including the cancerrelevant JMJD2C (GASC1). A detailed enzyme kinetic and inhibition analysis of these HDMs was achieved through a range of fluorescence assays, mass spectrometry, and oxygen consumption measurements. An interesting case of cosubstrate inhibition is observed for these HDMs, with direct relevance to the potential role of alpha-ketoglutarate and HDMs in cancer cells. We have also employed an enzyme-templated approach for specific inhibitor design that takes advantage of the enzyme s substrate specificity. Finally, while the initially tested compounds do not seem to inhibit JMJD2C in MCF7 breast cancer cells, we believe that second generation compounds will be active HDM inhibitors in vivo. The developed specific inhibitors could lead to novel breast cancer therapeutics and can also be used as tools for studying the role of histone demethylases in breast cancer cell proliferation.