Recognition of the CREB-Binding Protein/Mixed Lineage Leukemia Interface by Sulfonyl-γ-AApeptides: Beyond Mimicry of Mixed Lineage Leukemia

作者：Bo Huang, Minghui Wang, Emily Gregory‐Lott, Bingbing X. Li, Yu Yu Win, Ning Shen, Jianyu Chen, Sihao Li, Chuanhai Cao, Xiangshu Xiao, Gary W. Daughdrill, Jianfeng Cai · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01148 · 被引用次数：6 · 研究领域：Chemical Synthesis and Analysis、Protein Degradation and Inhibitors、Click Chemistry and Applications

The kinase-inducible (KIX) domain, a structured region within the transcriptional coactivators CREB-binding protein (CBP) and p300, serves as a docking site for multiple transcription factors, including the mixed lineage leukemia (MLL) protein. The MLL-KIX protein-protein interaction (PPI) has been implicated in various diseases, such as leukemia, cancer, and neurodegenerative disorders, including Alzheimer's disease. In this study, we developed a series of MLL-mimicking peptidomimetic foldamers based on a sulfonyl-γ-AApeptide backbone. These helical foldamers successfully mimic the folded transactivation domain (TAD) of MLL and bind the KIX domain with a high affinity. Consistent with the notion that MLL-KIX interaction can allosterically enhance CREB signaling, we found that the sulfonyl-γ-AApeptides strongly stimulate CREB-dependent gene expression. Moreover, they exhibit no significant cytotoxicity under the tested conditions, demonstrating both binding specificity and therapeutic potential for targeting CREB-related pathways in neurodegenerative disorders.