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  1. ; ; ; ; ; ; ; ; ; ; et al (, ChemBioChem)
    Abstract Natural products are often uniquely suited to modulate protein‐protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (KD1 μM) with a non‐canonical binding site containing a structurally dynamic loop in CBP/p300 KIX. Garcinolic acid engages full‐length CBP in the context of the proteome and in doing so effectively inhibits KIX‐dependent transcription in a leukemia model. As the most potent small‐molecule KIX inhibitor yet reported, garcinolic acid represents an important step forward in the therapeutic targeting of CBP/p300. 
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