2. Academic Validation
  3. Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain

Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain

  • Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):E7786-E7794. doi: 10.1073/pnas.1805020115.
Whitney R Grither 1 2,  Gregory D Longmore 3 4 5
Affiliations

Affiliations

  • 1 Integrating Communication within the Cancer Environmental Institute, Washington University, St. Louis, MO 63110.
  • 2 Department of Biochemistry and Biophysics, Washington University, St. Louis, MO 63110.
  • 3 Integrating Communication within the Cancer Environmental Institute, Washington University, St. Louis, MO 63110; glongmore@wustl.edu.
  • 4 Department of Medicine, Washington University, St. Louis, MO 63110.
  • 5 Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110.
PMID: 30061414 DOI: 10.1073/pnas.1805020115
Abstract

The action of the collagen binding receptor tyrosine kinase (RTK) Discoidin Domain Receptor 2 (DDR2) in both tumor and tumor stromal cells has been established as critical for breast Cancer metastasis. Small molecule inhibitors that target the extracellular domain of RTKs are rare, as they have classically been regarded as too small to block binding with large polypeptide ligands. Here, we report the identification and characterization of a selective, extracellularly acting small molecule inhibitor (WRG-28) of DDR2 that uniquely inhibits receptor-ligand interactions via allosteric modulation of the receptor. By targeting DDR2, WRG-28 inhibits tumor invasion and migration, as well as tumor-supporting roles of the stroma, and inhibits metastatic breast tumor cell colonization in the lungs. These findings represent an approach to inhibiting tumor-stromal interactions and support the development of allosteric inhibitors of DDR2, such as WRG-28, as a promising approach to antimetastasis treatment.

Keywords

DDR2; allosteric inhibition; metastasis.

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