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Click bait

GSK is using click chemistry to validate how and where its compounds work

GlaxoSmithKline plc is developing click chemistry-based systems to pinpoint and quantify how drug candidates target DNA sequences, protein complexes and disease sites. The company believes the "click-probes" could slash failure rates in drug development by validating target engagement.

The idea is that click chemistry -- which covalently links chemical groups without disrupting nearby biochemical reactions -- can be exploited to catch and report molecular interactions in situ, providing a snapshot of where candidate drugs are binding and how that influences surrounding molecules.

To develop the probing strategy, GSK tapped the chemoproteomics expertise of its Cellzome GmbH unit, acquired in 2012. Cellzome group leader Paola Grandi defined chemoproteomics as a way to monitor “the interaction of a molecule with a protein target under close to physiological conditions in ex vivo cells and tissues."

According to Grandi, her team and others had previously developed chemoproteomic methods to label compounds and pull down their targets using tags like biotinylated polyethylene glycol (PEG), but those bulky tags altered the compounds' cellular uptake and function. In contrast, click chemistry has the advantage of modifying “small molecule drugs minimally,” she said, allowing the team to tag compounds with functional groups like trans-cyclooctene or propargylamine, which have molecular masses of 110 Da and 55 Da, respectively.

"These modifier groups that are amenable to click chemistry are definitely among the smallest

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