Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep;13(9):994-1001.
doi: 10.1038/nchembio.2442. Epub 2017 Jul 24.

Peptidomimetic Inhibitors of APC-Asef Interaction Block Colorectal Cancer Migration

Affiliations

Peptidomimetic Inhibitors of APC-Asef Interaction Block Colorectal Cancer Migration

Haiming Jiang et al. Nat Chem Biol. .

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.

Similar articles

See all similar articles

Cited by 13 articles

See all "Cited by" articles

References

    1. J Cell Sci. 2007 Oct 1;120(Pt 19):3327-35 - PubMed
    1. Biochim Biophys Acta. 2017 Apr;1859(4):577-585 - PubMed
    1. World J Gastroenterol. 2005 Sep 28;11(36):5651-4 - PubMed
    1. Nat Commun. 2016 Mar 24;7:11040 - PubMed
    1. Science. 2000 Aug 18;289(5482):1194-7 - PubMed

MeSH terms

Substances

Feedback