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

  • J Med Chem. 2018 Sep 13;61(17):8017-8028. doi: 10.1021/acs.jmedchem.8b01112.
Xiuyan Yang ,  Jie Zhong ,  Qiufen Zhang ,  Jinxing Qian ,  Kun Song ,  Cong Ruan ,  Jianrong Xu ,  Ke Ding  1 ,  Jian Zhang
Affiliations
  • 1. School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.
PMID: 30095910 DOI: 10.1021/acs.jmedchem.8b01112
Abstract

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 ( Kd = 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-126016
    MAI-400
    APC-Asef Interaction Inhibitor
    target: APC
    Research Areas: Cancer