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

The 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 (K(d) = 0.0...

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Autores principales: Zhong, Jie, Guo, Yuegui, Lu, Shaoyong, Song, Kun, Wang, Ying, Feng, Li, Zheng, Zhen, Zhang, Qiufen, Wei, Jiacheng, Sang, Peng, Shi, Yan, Cai, Jianfeng, Chen, Guoqiang, Liu, Chen-Ying, Yang, Xiuyan, Zhang, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402538/
https://www.ncbi.nlm.nih.gov/pubmed/36002443
http://dx.doi.org/10.1038/s41467-022-32612-6
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author Zhong, Jie
Guo, Yuegui
Lu, Shaoyong
Song, Kun
Wang, Ying
Feng, Li
Zheng, Zhen
Zhang, Qiufen
Wei, Jiacheng
Sang, Peng
Shi, Yan
Cai, Jianfeng
Chen, Guoqiang
Liu, Chen-Ying
Yang, Xiuyan
Zhang, Jian
author_facet Zhong, Jie
Guo, Yuegui
Lu, Shaoyong
Song, Kun
Wang, Ying
Feng, Li
Zheng, Zhen
Zhang, Qiufen
Wei, Jiacheng
Sang, Peng
Shi, Yan
Cai, Jianfeng
Chen, Guoqiang
Liu, Chen-Ying
Yang, Xiuyan
Zhang, Jian
author_sort Zhong, Jie
collection PubMed
description The 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 (K(d) = 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 IC(50) 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.
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spelling pubmed-94025382022-08-26 Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors Zhong, Jie Guo, Yuegui Lu, Shaoyong Song, Kun Wang, Ying Feng, Li Zheng, Zhen Zhang, Qiufen Wei, Jiacheng Sang, Peng Shi, Yan Cai, Jianfeng Chen, Guoqiang Liu, Chen-Ying Yang, Xiuyan Zhang, Jian Nat Commun Article The 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 (K(d) = 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 IC(50) 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. Nature Publishing Group UK 2022-08-24 /pmc/articles/PMC9402538/ /pubmed/36002443 http://dx.doi.org/10.1038/s41467-022-32612-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhong, Jie
Guo, Yuegui
Lu, Shaoyong
Song, Kun
Wang, Ying
Feng, Li
Zheng, Zhen
Zhang, Qiufen
Wei, Jiacheng
Sang, Peng
Shi, Yan
Cai, Jianfeng
Chen, Guoqiang
Liu, Chen-Ying
Yang, Xiuyan
Zhang, Jian
Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors
title Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors
title_full Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors
title_fullStr Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors
title_full_unstemmed Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors
title_short Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors
title_sort rational design of a sensitivity-enhanced tracer for discovering efficient apc–asef inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402538/
https://www.ncbi.nlm.nih.gov/pubmed/36002443
http://dx.doi.org/10.1038/s41467-022-32612-6
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