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Study Highlights Role of Protein Complexes in Epigenetic Drug Interactions

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Interactions between histone deacetylases and drugs that inhibit these enzymes vary, in part, depending on the protein complex in which an HDAC is found, according to a study appearing online yesterday in Nature Biotechnology.

Researchers from Cellzome in Germany and the UK used their chemoproteomics approach, dubbed Episphere, to identify the sub-proteomes associated with more than a dozen selective histone deacetylase inhibitors — and explore the selectivity of these HDAC inhibitors.

They found that the sets of proteins that interact with various HDAC inhibitors shift depending on both the HDAC being targeted and its larger protein complex, leading them to argue that "the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits."

"The scientific and drug discovery community may need to revise their concept of a 'drug target' to include consideration not just of the target protein but also of the protein's associated complex, as we continue to learn more about the subtle interactions between drugs and proteins in their natural environments rather than as purified enzymes," senior author Gerard Drewes, vice president of discovery research at Cellzome, said in a statement.

With a host of studies exploring the role that epigenetics plays in health and disease, researchers are increasingly interested in finding beneficial ways to tweak epigenetic profiles. For instance, Drewes and his co-authors noted, over the past decade-and-a-half, compounds that curb the activity of HDACs have been garnering interest as potential treatments for everything from cancer to autoimmune and neurodegenerative disease.

Even so, they explained, more research is needed to understand how specific HDAC inhibitors interact with their targets and the consequences of these interactions.

Last year, Cellzome entered into an agreement with GlaxoSmithKline that involves the use of Cellzome's Episphere approach for finding auto-inflammatory immune disease drug targets from the four HDAC classes.

These enzymes are grouped based on their sequence phylogeny and function, the researchers explained, though the complexes formed by specific HDACs can vary from one cell type to the next.

"HDACs form the catalytic core of megadalton complexes involved in chromatin modification and gene repression," they wrote. "The roles of these complexes are diverse and often cell-type specific."

For the current study, the team used their chemoproteomics approach to look at the protein complexes bound by 16 different HDAC inhibitors using a combination of affinity capture and quantitative mass spectrometry. To do this, the team first designed chemical probes directed against particular HDAC classes. They then exposed these so-called target class-specific probes to cell extracts and used mass spectrometry to compare protein interactions in cells treated with HDAC inhibitors with those from untreated cells.

"The reduction in protein capture that resulted from inhibitor treatment was quantified by isobaric tagging of tryptic peptides and tandem mass spectrometry analysis (MS/MS) of the combined peptide pools," they explained. "For each identified protein, the decrease of the reporter ion signals relative to the vehicle control reflects the competitive binding of the 'free' inhibitor to its target."

Overall, the researchers found that HDAC inhibitor interactions with specific protein sub-units tended to shift depending on the makeup of the larger protein complex in which these sub-units were found.

"This publication demonstrates how important it is to measure the action of drugs in the physiological context in which the targets operate," Cellzome CEO Tim Edwards, who was not directly involved in the study, said in a statement.

Moreover, the team demonstrated how their approach could be used to not only assess sub-proteome associations in different cell types under different conditions, but also for tracking down new potential HDAC inhibitors.

"[W]e have shown that a chemoproteomics strategy based on small-molecule inhibitors can be applied to discover and classify molecular complexes around drug target proteins, which has not, to our knowledge, been previously shown," they concluded. "The data support the value of drug discovery strategies based on target proteins in their biological context."

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