Matrix metalloproteinase inhibitor reduces cancer invasion
Matrix metalloproteinase-9, or MMP-9, remodels the extracellular matrix, but its dysregulation contributes to many diseases, including metastatic cancer. Efforts to develop MMP-9 inhibitors to treat cancer have been hampered by small molecules’ poor specificity and side effects from blocking other MMPs with similar catalytic domains. Tissue inhibitors of metalloproteinases, or TIMPs, block multiple MMPs, but tweaking their specificity is possible since some MMPs have unique domains that interact with larger protein inhibitors. Alireza Shoari at the Mayo Clinic and a team in the U.S. aimed to target the MMP-9 fibronectin domain for TIMP binding. They published their recent study in the Journal of Biological Chemistry.

Using yeast surface display, the team screened a large library in a directed evolution experiment to identify a TIMP-1 variant with enhanced binding to the MMP-9 catalytic and fibronectin domains. They selected the strongest binder, TIMP-1-C15, and confirmed its MMP-9 inhibition in enzyme assays. The authors demonstrated that TIMP-1-C15 inhibition decreases if the fibronectin domain is removed, providing evidence that the fibronectin domain heavily contributes to the interaction.
Flow cytometry and dose-dependent inhibition assays showed that TIMP-1-C15 selectively binds and inhibits MMP-9 over MMP-1, -2 and -3, even though MMP-2 contains a similar fibronectin domain. In cell invasion assays with triple-negative breast cancer cells that require MMP-9, TIMP-1-C15 reduced cell invasion at least as well, or slightly better, compared to unmodified TIMP-1.
Future structural studies will reveal how TIMP-1-C15 binds MMP-9’s fibronectin domain over MMP-2’s similar domain. In addition, animal model testing will help determine TIMP-1-C15’s potential to treat metastatic cancer.
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