Creative screening for drug targets

A team of scientists has introduced a new approach for discovering drugs that target epigenetic regulators, which can be involved in various diseases from developmental abnormalities to cancer.

DNA in cells is wrapped around proteins called histones that form structures known as nucleosomes. In turn nucleosomes can fold further into higher order structures, burying DNA within them. The accessibility of DNA is hindered by being buried in such structures, which adds another layer of regulation to whether genes are expressed or not, above the genetic layer, known as “epi-genetics“ — literally meaning above genetics. 

Gene expression levels, among other factors, influence whether or not these structures open to expose DNA. In diseases such as cancer, genes responsible for uncontrolled proliferation of cells are overexpressed, possibly because proteins that regulate their burial within these structures are deregulated. 

Automatically, these proteins become potential drug targets for cancer therapeutics and other diseases. It’s why the authors of this new study set out to find drugs targeting proteins that recognize epigenetic marks. However, instead of having a single target in mind, they screened hundreds of small compounds, and proteins, looking for both a good potential target, and a good drug candidate for it; what they refer to as “target hopping”. 

Their experimental set-up consisted of a chip on which hundreds of domains from different protein factors known to recognize epigenetic marks were fixed. They screened small molecules, which can potentially bind and inhibit any of these domains, tagged with a fluorescent dye. 

By locating the position of the fluorescence signal on the chip, they can then identify which protein the small molecule targets. 

They managed to identify a new drug showing that their “target hopping” strategy has potential for exploratory drug discovery studies. 

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