Researchers at the University of Toronto Mississauga have devised a way to split up a dangerous pair of cancer proteins meaning that chemotherapy that is more effective and has fewer side effects may be around the corner.
The breakthrough work was carried out in collaboration with researchers at the University of Central Florida and the Princess Margaret Hospital.
The researchers have created several molecules that inhibit Stat3, a protein that pairs with another copy of itself in cancer cells, and goes haywire.
"The molecules we have created are particularly nice because they're showing selectivity against cancer cells but not against healthy cells. This molecule could be used in conjunction with typical chemotherapeutics, and it could mean that drugs will have less resistance-so you could use lower dosages and cause fewer side effects," says senior study author Professor Patrick Gunning, of the Department of Chemical and Physical Sciences at the University of Toronto Mississauga.
The Stat3 protein is involved in almost all cancers, and is known to contribute to the resistance of cancer cells to current drug therapies.
"Most currently available therapeutics aim to induce cell death. We wanted to make small molecules that could try and stop this protein," says Gunning.
In cancerous cells, Stat3 proteins bind together to work as a lethal pair, and inhibitors work to prevent this. This type of protein-protein interaction is notoriously difficult to counter.
During the study, Gunning and his colleagues targeted binding "hotspots" on a known Stat3 inhibitor called S3I-201.
The researchers chemically altered the inhibitor to produce several new variants, which they then tested on Stat3.
They found that some variants were even more powerful than S3I-201, and showed activity against prostate, breast and acute myeloid leukemia cancer cell lines.
"These are some of the most potent inhibitors in the literature so far for this particular protein. In some cases, they were more than twice as effective as the existing inhibitor," says Gunning.
Upon using more complex cancer cell models, the researchers found that the inhibitors survived the passage across the cell membrane, and still targeted the Stat3 cancer proteins inside.
The researchers are working to make the new inhibitors even more effective, as well as more metabolically stable, meaning that they can survive the chemical defence mechanisms within the cell.
They are currently studying the use of their new inhibitors alongside traditional chemotherapy drugs.
The findings they have made thus far have been reported in ChemBioChem: A European Journal of Chemical Biology.