Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA.
Program in Chemical Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA.
Chembiochem. 2023 Nov 2;24(21):e202300439. doi: 10.1002/cbic.202300439. Epub 2023 Sep 7.
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 (K 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.
天然产物通常因其结构和官能团的复杂性相对于合成分子而特别适合调节蛋白质-蛋白质相互作用（PPIs）。在这里，我们证明天然产物 Garcinol 酸别构地阻断 CBP/p300 KIX PPI 网络，并显示出对相关 GACKIX 基序的优异选择性。它通过与包含 CBP/p300 KIX 中结构动态环的非典型结合位点的强相互作用（K 1 μM）来实现这一点。Garcinol 酸在蛋白质组的背景下与全长 CBP 结合，并在白血病模型中有效抑制 KIX 依赖性转录。作为迄今为止报道的最有效的小分子 KIX 抑制剂，Garcinol 酸代表了在 CBP/p300 的治疗靶向方面向前迈出的重要一步。
