Human fascin complexed with macroketone, PDB ID=3LNA The deadliest feature of cancer is its ability to spread, or metastasise. Migrastatin, a compound isolated from Streptomyces, was found to weakly inhibit tumour cell migration and, in 2005, researchers from Weill Medical College of Cornell University and the Sloan-Kettering Institute for Cancer Research described simplified analogues of migrastatin, including a compound they called macroketone, that inhibit mammary tumour metastasis in mice. Although the compounds were effective in preventing the spread of cancer cells, it wasn’t known how they achieved this. In a new study, published in the journal Nature, the team have revealed that macroketone exerts its anti-metastatic effect by targeting the actin-bundling protein, fascin. Cancer cells use invasive finger-like protrusions called invadopodia to spread into and degrade extracellular matrix and recent studies have shown that fascin is important for their assembly and stability.
Macroketone Mice implanted with cancer cells and treated with macroketone lived out a full lifespan without any spread of the cancer whilst untreated animals all died from metastases. When treatment was delayed for one week after introduction of the cancer cells, metastasis was still blocked by more than 80%. Macroketone did not prevent implanted cancer cells from forming tumours or growing, suggesting that such compounds would need to be used in combination with chemotherapy drugs acting on the primary tumour. Because fascin is overexpressed in metastatic tumour cells but is only expressed at very low levels in normal epithelial cells, treatments that target fascin should have comparatively little effect on normal cells and may have fewer side effects than other treatments.
X-ray studies showed that macroketone binds to one of the actin-binding sites on fascin which prevents the actin fibres from bundling together and could form the basis for further drug design.
