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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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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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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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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DOI: https://doi.org/10.1038/nchembio.2442
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