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J Am Chem Soc. 2017 Nov 15;139(45):16056-16059. doi: 10.1021/jacs.7b08972. Epub 2017 Nov 1.

Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction.

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Department of Chemistry and Division of Advanced Material Science, Pohang University of Science and Technology (POSTECH) , Pohang 37673, South Korea.
New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation , Daegu 41061, South Korea.
Division of Integrative Biosciences & Biotechnology, POSTECH , Pohang 37673, South Korea.
Academy of Immunology and Microbiology, Institute for Basic Science (IBS) , Pohang 37673, South Korea.


The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.

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