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Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from  Garcinia speciosa , that inhibit the Notch signaling pathway.  HES1  and  HES5  are target genes of the Notch cascade, and compound  2 , referred to as cowanin, decreased the protein levels of HES1 and HES5 in assay cells. Furthermore, cowanin ( 2 ) showed potent cytotoxicity against human leukemic HPB-ALL cells. The Notch signaling inhibitory activity of cowanin ( 2 ) is linked to the increased degradation of nicastrin, which is one of the components of the γ-secretase complex. To the best of our knowledge, this is the first example of a compound with Notch pathway inhibitory activity mediated by nicastrin degradation.

The Notch inhibitor cowanin accelerates nicastrin degradation