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

Jie Zhong, Yuegui Guo, Shaoyong Lu, Kun Song, Ying Wang, Li Feng, Zhen Zheng, Qiufen Zhang, Jiacheng Wei, Peng Sang, Yan Shi, Jianfeng Cai, Guoqiang Chen, Chen-Ying Liu (), Xiuyan Yang () and Jian Zhang ()
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Jie Zhong: Shanghai Jiao Tong University School of Medicine
Yuegui Guo: Shanghai Jiao Tong University School of Medicine
Shaoyong Lu: Shanghai Jiao Tong University School of Medicine
Kun Song: Shanghai Jiao Tong University School of Medicine
Ying Wang: Shanghai Jiao Tong University School of Medicine
Li Feng: Shanghai Jiao Tong University School of Medicine
Zhen Zheng: Shanghai Jiao Tong University School of Medicine
Qiufen Zhang: Shanghai Jiao Tong University School of Medicine
Jiacheng Wei: Shanghai Jiao Tong University School of Medicine
Peng Sang: University of South Florida
Yan Shi: University of South Florida
Jianfeng Cai: University of South Florida
Guoqiang Chen: Chinese Academy of Medical Sciences
Chen-Ying Liu: Shanghai Jiao Tong University School of Medicine
Xiuyan Yang: Shanghai Jiao Tong University School of Medicine
Jian Zhang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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 (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.

Date: 2022
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DOI: 10.1038/s41467-022-32612-6

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