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

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  • Jie Zhong

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    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
    University of Macau)

  • Jian Zhang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    Zhengzhou University)

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.

Suggested Citation

  • 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 & Ji, 2022. "Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32612-6
    DOI: 10.1038/s41467-022-32612-6
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    1. Lu Lu & Qi Liu & Yun Zhu & Kwok-Hung Chan & Lili Qin & Yuan Li & Qian Wang & Jasper Fuk-Woo Chan & Lanying Du & Fei Yu & Cuiqing Ma & Sheng Ye & Kwok-Yung Yuen & Rongguang Zhang & Shibo Jiang, 2014. "Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
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