New molecules to stop breast cancer proliferation
The Wnt signaling pathway is a cascade of chemical reactions often dysregulated in cancer. The discovery of new agents capable of inhibiting it would provide novel therapeutic approaches to treat cancer. Such drugs are particularly needed to treat triple negative breast cancer, an aggressive disease that accounts for a third of the breast cancer deaths.
New inhibitors of the Wnt pathway
Researchers from the laboratory of Prof. Vladimir Katanaev used an interdisciplinary approach combining both chemistry and biology to find novel small molecules inhibiting the Wnt signaling pathway. They screened thousands of compounds and, after validation and further characterization, they were able to identify an interesting small molecule able to block the pathway in a triple-negative breast cancer cell line(compound 4a in the Figure below).
From that first molecule, the interdisciplinary team synthesized dozens of variations (two example variations in the Figure below) to understand which part of the compound was responsible for the inhibition and improve its effect. These variations led to an improvement in inhibition activity of up to 10-fold (see the decrease of the concentrations needed to obtain a 50% inhibition, IC50 values, in the Figure below).
Chemical structure of the firstly inhibitor identified (on the left) and of two other promising inhibitors synthesized on the basis of the first. IC50 values indicate the concentrations needed to reach 50% inhibition of the signal. © UNIGE -Laboratory of Prof. Vladimir Katanaev
Do the compounds also work in other cell lines?
The scientists then checked whether their compounds could inhibit the Wnt signaling pathway in other triple-negative breast cancer cell lines. They found that they were able to inhibit both Wnt signaling and cell proliferation in another cell line, without affecting a non-cancerous breast cell line. Moreover, they also observed synergic effect with a standard treatment of breast cancer, docetaxel. These promising findings open up new avenues to broaden therapeutic options against triple-negative breast cancer.
5 Dec 2022