Fishing for new anti-cancer drugsby Leigh MacMillan Sep. 18, 2013, 8:00 AM
The Wnt/beta-catenin signaling pathway plays critical roles in embryonic development, including in dorsoventral (back-to-front) patterning in zebrafish. Because aberrant Wnt/beta-catenin activation is thought to cause a number of human diseases, especially cancers, pharmaceutical companies and academic investigators are actively seeking small molecules that inhibit this signaling pathway.
Charles Hong, M.D., Ph.D., associate professor of Medicine, and colleagues devised an in vivo zebrafish screen to identify small molecules that perturb dorsoventral patterning – and therefore might be Wnt inhibitors. In the Sept. 12 issue of Cell Reports, they describe the discovery of windorphen, a small molecule that blocks the Wnt signaling required for ventral development. They showed that windorphen selectively inhibits p300 histone acetyltransferase, a molecule that associates with beta-catenin to regulate gene expression – but that it does not block another beta-catenin-associated protein called CBP. They also demonstrated that windorphen kills cancer cells with activated Wnt signaling.
The findings suggest that windorphen and other small molecules that target the p300 protein may offer therapeutic advantages as anti-cancer agents.
This research was supported by a Veterans Administration Merit Award, a Developmental Grant from the Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders, and grants from the National Institutes of Health (HL104040, HL100398, GM081635, GM103926, CA095103).