当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Rational Design and Structure Validation of a Novel Peptide Inhibitor of the Adenomatous-Polyposis-Coli (APC)-Rho-Guanine-Nucleotide-Exchange-Factor-4 (Asef) Interaction.

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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Yang X,Zhong J,Zhang Q,Qian J,Song K,Ruan C,Xu J,Ding K,Zhang J

doi

10.1021/acs.jmedchem.8b01112

subject

Has Abstract

pub_date

2018-09-13 00:00:00

pages

8017-8028

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

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