Breen, M. E.; Joy, S. T.; Baruti, O. J.; Beyersdorf, M. S.; Henley, M. J.; DeSalle, S. N.; Ycas, P. D.; Croskey, A.; Cierpicki, T.; Pomerantz, W. C. K.; Mapp, A. K. "Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks." ChemBioChem, 2023, 24, e202300439.
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 (KD 1 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.