Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors-Reference-Cited by-同舟云学术

Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors

Published:2022-08-24 Issue:1 Volume:13 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

Zhong Jie,Guo Yuegui,Lu Shaoyong^ORCID,Song Kun,Wang Ying,Feng Li,Zheng Zhen,Zhang Qiufen,Wei Jiacheng,Sang Peng,Shi Yan,Cai Jianfeng^ORCID,Chen Guoqiang^ORCID,Liu Chen-Ying^ORCID,Yang Xiuyan^ORCID,Zhang Jian^ORCID

Abstract

AbstractThe adenomatous polyposis coli (APC)–Rho guanine nucleotide exchange factor 4 (Asef) protein–protein interaction (PPI) is essential for colorectal cancer metastasis, making it a promising drug target. Herein, we obtain a sensitivity-enhanced tracer (tracer 7) with a high binding affinity (Kd = 0.078 μM) and wide signal dynamic range (span = 251 mp). By using tracer 7 in fluorescence-polarization assays for APC–Asef inhibitor screening, we discover a best-in-class inhibitor, MAI-516, with an IC50 of 0.041 ± 0.004 μM and a conjugated transcriptional transactivating sequence for generating cell-permeable MAIT-516. MAIT-516 inhibits CRC cell migration by specifically hindering the APC–Asef PPI. Furthermore, MAIT-516 exhibits no cytotoxic effects on normal intestinal epithelial cell and colorectal cancer cell growth. Overall, we develop a sensitivity-enhanced tracer for fluorescence polarization assays, which is used for the precise quantification of high-activity APC–Asef inhibitors, thereby providing insight into PPI drug development.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Link

https://www.nature.com/articles/s41467-022-32612-6.pdf

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