Positive Selection Screen for Natural Product β-Catenin Inactivators

We reasoned that these concerns could be partly mitigated by screening prefractionated natural product mixtures in cell-based “up” assays. We tested 326,304 natural product mixtures (40,744 extracts and 285,560 fractions derived from them) in a high throughput screen using mammalian cells expressing an oncogenic version of β-catenin (β-cat) fused to a suicide protein.

Multiple fractions degraded the β-cat fusion protein or drove it into a compartment where both fusion partners were apparently inactive. The active compound from one of the latter specifically activates novel, but not classical, protein kinase Cs (PKCs) and thereby relocates β-cat to juxtamembrane vacuolar structures. These findings suggest a path for inactivating oncogenic β-cat and underscore the power of natural product screening.