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Peptidomimetic inhibitors of APC–Asef interaction block colorectal cancer migration

Nature Chemical Biology volume 13, pages 994–1001 (2017)Cite this article

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Abstract

The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC–Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC–Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein–protein interaction inhibitors available for the development of cancer therapeutics targeting APC–Asef signaling.

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Figure 1: Design, competitive binding activities, and co-crystal structures of first-generation peptides complexed with APC.
Figure 2: Characterization and co-crystal structure of MAI-150 complexed with APC.
Figure 3: The binding activity and co-crystal structure of MAI-203 complexed with APC.
Figure 4: MAITs inhibit APC–Asef interaction in cells.
Figure 5: MAITs inhibit the migration and invasion of SW480 cells.
Figure 6: MAIT-203 inhibits APC–Asef-mediated CDC42 activation in SW480 cells and in vitro.

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Acknowledgements

We sincerely thank T. Akiyama (University of Tokyo) for help with the cell migration assay and for fruitful discussions on application, S. Wang (University of Michigan) for design discussion and antibody shipping, and the Shanghai Synchrotron Radiation Facility (SSRF) for crystal diffraction. APC, Asef and full-length CDC42 were kind gifts from G. Wu (Shanghai Jiao-Tong University, Shanghai, China). This work was supported in part by the National Basic Research Program of China (973 Program) (grant 2015CB910403 to J.Z.), the National Natural Science Foundation of China (grants 81630075 to J.Y., 81322046 and 81473137 to J.Z., and 81302698 to S.L.), the Innovative Research Group of NSFC (J.Z., J.Y. and G.C.), the Shanghai Rising-Star Program (grant 13QA1402300 to J.Z.), the Shanghai Sailing Program (grant 17YF1410600 to X.Y.), the National Program for Support of Top-notch Young Professionals (grant 2015 to J.Z.), and the Program for New Century Excellent Talents in University (grant NCET-12-0355 to J.Z.).

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  1. Haiming Jiang, Rong Deng and Xiuyan Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Haiming Jiang, Rong Deng, Xiuyan Yang, Jialin Shang, Shaoyong Lu, Yanlong Zhao, Kun Song, Xinyi Liu, Qiufen Zhang, Guoqiang Chen, Jianxiu Yu & Jian Zhang

  2. Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Rong Deng & Jianxiu Yu

  3. Medicinal Bioinformatics Center, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Xinyi Liu, Qiufen Zhang & Jian Zhang

  4. State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, China

    Yu Chen

  5. Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Y Eugene Chinn & Guoqiang Chen

  6. State Key Laboratory of Microbial Metabolism, Shanghai Jiao-Tong University, Shanghai, China

    Geng Wu

  7. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China

    Jian Li

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  1. Haiming Jiang
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Contributions

J.Z. designed the research project. J.Z., H.J., R.D., X.Y., J.S., S.L., X.L., G.C., and J.Y. performed the biological experiments and analyzed data. Y.Z. and K.S. performed the crystallography. X.Y. carried out peptide synthesis, purification and characterization. Y.C., Y.E.C., Q.Z., G.W., and J.L. generated key protein reagents. K.S. solved the crystal structures. All authors contributed to the manuscript, with J.Z. and J.Y. assuming responsibility for the manuscript in its entirety.

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Correspondence to Jianxiu Yu or Jian Zhang.

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Jiang, H., Deng, R., Yang, X. et al. Peptidomimetic inhibitors of APC–Asef interaction block colorectal cancer migration. Nat Chem Biol 13, 994–1001 (2017). https://doi.org/10.1038/nchembio.2442

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