Rational Design and Structure Validation of a Novel Peptide Inhibitor of the Adenomatous-Polyposis-Coli (APC)–Rho-Guanine-Nucleotide-Exchange-Factor‑4 (Asef) Interaction

• Published in: Journal of medicinal chemistry 2018-09, Vol.61 (17), p.8017-8028
• Main Authors: Yang, Xiuyan, Zhong, Jie, Zhang, Qiufen, Qian, Jinxing, Song, Kun, Ruan, Cong, Xu, Jianrong, Ding, Ke, Zhang, Jian
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01112

In colorectal cancer, adenomatous polyposis coli (APC) interacts with Rho guanine-nucleotide-exchange factor 4 (Asef), thereby stimulating aberrant colorectal-cancer-cell migration. Consequently, the APC–Asef interaction represents a promising therapeutic target for mitigating colorectal-cancer migration. In this study, we adopted the rational-design strategy involving the introduction of intramolecular hydrogen bonds and optimization of the lipophilic substituents to improve the binding affinities of peptides, leading to the discovery of MAI-400, the best inhibitor of the APC–Asef interaction known to date (K d = 0.012 μM, IC50 = 0.25 μM). Comprehensive evaluation of MAI-400 by biochemical and biophysical assays revealed the formation and effect of an intramolecular hydrogen bond. A cell-based assay showed MAI-400 efficiently blocking the APC–Asef interaction in a dose-dependent manner. Therefore, our study provides a best-in-class inhibitor, MAI-400, based on the rational drug design and structural validation, that can effectively inhibit the APC–Asef interaction.