Canadian researchers have identified unexpected drug activities by probing biochemical pathways inside living cells.

'It is a different way of doing things,' said team member Stephen Michnick at the University of Montreal. 'This is the first report of the strategy performed on this scale,' he told Chemistry World.

Patterns of gene expression are currently used to predict drug activity, and can provide hypotheses about the cellular mechanisms of drug responses. But changes in mRNA expression do not always correlate with the level or activity of corresponding proteins, says Michnick, and the complexity of gene regulation can obscure the mechanisms of action of drugs within biochemical pathways.

Michnick and colleagues screened over 100 drugs covering six therapeutic areas. They used the proteomics technique of high-content protein-fragment complementation assay (PCA), which measures protein-protein interactions in biological systems. The assays incorporate a fluorescent protein that enables measurement of the spatial and temporal changes of protein interactions.

The strategy turned up some unexpected anticancer activities of drugs developed for other disorders. For example, said Michnick, the antidepressant, sertraline. 

Sertraline: (1S)-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride

'This was a bit of a surprise, we didn't really set out to demonstrate this but early results were suggestive and follow up revealed that the screen was predicting drugs that could have anti-growth activity against some cancer cells,' said Michnick, adding that this is a long way from proving that these drugs would be effective anticancer drugs.

Biotechnologist George Miklos, founder and director of the Australian biomedical advisory service Secure Genetics, has previously highlighted drawbacks of analysing microarray-based gene expression data. The problem, he says, is separating genes causally involved in a disease from innocent bystander genes, whose expression levels have been secondarily altered by primary changes elsewhere. Miklos told Chemistry World that Michnick's paper made for 'very interesting reading.'

The work was performed at Odyssey Thera, a biotech firm in California, US that was spun out of Michnick's lab in Montreal. 'Odyssey are actively using this approach for pharmaceutical company partners,' said Michnick.
Bea Perks

References

M L MacDonald et al, Nat. Chem. Biol., (DOI:10.1038/nchembio790)