Bioactive terpenoids from the Bahaman sponge Smenospongia aurea

Sixty percent of colon cancers exhibit PTEN loop mutations which makes this mutation a valuable target for cancer chemotherapeutics. Recently, ENTPD5, a regulator of protein N-glycosylation and of proper protein folding in the ER of cells exhibiting mutations in the AKT/PTEN pathway, was suggested to provide a therapeutic intervention in PTEN driven colon tumors. In a high throughput screen to look for small molecule inhibitors of ENTPD5, we identified extracts from the marine sponge Smenospongia aurea that had potent inhibitory activity. Using bioassay guided fractionation we isolated and characterized a family of diterpene natural products that inhibit ENTPD5, the most potent, chromozonarol, has a 10uM IC₅₀ (figure below). This poster will describe the isolation, characterization, and biological activity of this class of compounds.