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Cell-based phenotypic screening of natural product mixtures can reveal new biological and pharmacological principles but has been largely abandoned, partly because such mixtures can be difficult to deconvolute and often contain toxins that confound "down" assays. 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.