Complementary approaches to study histone lysine demethylases (KDM) for drug discovery

The interest in dissecting the relevance of different jumonji domain (JMJ)-containing KDMs as therapeutic targets in cancer and human disease is continuously increasing. Despite an increased interest in these proteins, a dearth of potent, selective and cell-permeable inhibitors remains. Here we describe the application of a novel AlphaScreen assay for measuring the catalytic activity of KDMs, and development and optimization of a quantitative cell-based target engagement assay to measure the effect of the demethylase activity in the chromatin of cancer cells. This high-throughput fluorescence platform allows monitoring of the ability of small molecules to inhibit KDM proteins from histone demethylation. These assays can be easily miniaturized and converted into high throughput screening format. Our biochemical and cellular assays are critical in supporting drug discovery efforts to generate potent, specific and cell active Jumonji inhibitors, delivering on the promise of epigenetic-based cancer therapies.

Poster presented by Grainne Gernon at ELRIG Drug Discovery 2015 (Telford, UK)

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