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Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration

Haiming Jiang1, Rong Deng1,2, Xiuyan Yang1

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

Nature Chemical Biology
|August 1, 2017
PubMed

Insights

Researchers developed novel peptidomimetics that inhibit adenomatous polyposis coli (APC) and Asef interaction, crucial for colorectal cancer cell migration. This discovery offers a new therapeutic strategy targeting cancer metastasis.

Area of Science:

  • Molecular oncology
  • Cancer cell biology
  • Drug discovery

Background:

  • Adenomatous polyposis coli (APC) binding to Asef receptor dysregulates Asef, promoting aberrant cell migration in colorectal cancer.
  • The APC-Asef interaction is a key driver of metastatic dissemination, making it a promising therapeutic target.

Purpose of the Study:

  • To design and develop peptidomimetics as potent inhibitors of the APC-Asef protein-protein interaction.
  • To investigate the role of APC-Asef signaling in colorectal cancer cell migration.
  • To identify downstream effectors involved in APC-stimulated Asef activation.

Main Methods:

  • Rational design of peptidomimetics targeting the APC interface.
  • Biochemical and cellular assays to evaluate inhibitor efficacy.
  • Crystal structure analysis to elucidate binding modes.
  • Utilized peptidomimetic as a chemical probe to identify downstream signaling components.

Main Results:

  • Designed peptidomimetics effectively inhibited the APC-Asef interaction within the APC binding pocket.
  • Inhibition of APC-Asef interaction led to reduced colorectal cancer cell migration.
  • Identified CDC42 as the downstream GTPase mediating APC-stimulated Asef activation.

Conclusions:

  • Targeting the APC-Asef interaction is a feasible strategy to regulate colorectal cancer cell migration.
  • Developed the first class of protein-protein interaction inhibitors for targeting APC-Asef signaling in cancer therapeutics.
  • Provides a novel chemical probe for studying APC-Asef pathway in colorectal cancer.

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