Discovery of peptidomimetic inhibitors of CREB/CBP by targeting hydrophobic grooves on the surface of the CBP KIX domain

https://doi.org/10.1016/j.apsb.2025.08.023

This new article publication from Acta Pharmaceutica Sinica B, discusses the discovery of peptidomimetic inhibitors of CREB/CBP by targeting hydrophobic grooves on the surface of the CBP KIX domain.

Cyclic AMP-response element binding protein (CREB), a downstream transcription factor of multiple signaling pathways, is overexpressed in many different types of cancers. Thus, targeting CREB has great potential for the development of antitumor agents. Peptidic foldamers have emerged as a powerful tool to disrupt disease-related protein–protein interactions (PPIs) with chemodiversity and high stability towards enzymatic degradation. The authors of this article harnessed several hydrophobic groups of helical sulfonyl-γ-AApeptide foldamer targeting the hydrophobic grooves on the surface of the KIX domain of CREB binding protein (CBP), to disrupt CREB/CBP PPI. It was demonstrated that several stapled sulfonyl-γ-AApeptides could suppress CREB-mediated gene transcription and exhibit effective antiproliferative activity in cell-based assays and demonstrate its potency in inhibiting tumor growth in vivo. This study suggests that sulfonyl-γ-AApeptides as a class of helical foldamer could mimic the helical kinase-inducible activation domain of CREB (KID) to target the hydrophobic grooves on the surface of CBP KIX domain, and thereby inhibiting KIX–KID interaction, which provides a new strategy for the development of antitumor agent by targeting PPIs involving intrinsically disordered proteins (IDPs).

Keywords: CREB/CBP interaction, KIX domain, IDPs, PPI inhibitors, Helical foldamers, Peptidomimetics, Sulfonyl-γ-AApeptides, Stapled peptides

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525005751-ga1_lrg.jpg

Stapled sulfonyl-γ-AApeptides selectively inhibit CREB/CBP interaction by targeting the KIX domain, offering a promising strategy to block transcription driven by intrinsically disordered proteins.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

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CiteScore: 24.3

Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy) 

JIF without self-citation: 13.8

ISSN 2211-3835

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Bo Huang, Emily Gregory-Lott, Bingbing X. Li, Timothy H. Tran, Sihao Li, Menglin Xue, Shaohui Wang, Anabanadam Asokan, Ning Shen, Xingming Sun, Chuanhai Cao, Xiangshu Xiao, Gary Daughdrill, Jianfeng Cai, Discovery of peptidomimetic inhibitors of CREB/CBP by targeting hydrophobic grooves on the surface of the CBP KIX domain, Acta Pharmaceutica Sinica B, Volume 15, Issue 12, 2025, Pages 6529-6545, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.08.023