Functional characterization of selective exosite-binding inhibitors of matrix metalloproteinase-13 (MMP-13) - Experimental validation in human breast and colon cancer

Abstract

© 2016 Japan Society for Bioscience, Biotechnology, and Agrochemistry.Considering the pathological significance of MMP-13 in breast and colon cancers, exosite-based inhibition of the C-terminal hemopexin (Hpx) domain could serve as an alternative strategy to develop selective inhibitors for MMP-13. Two of six lead compounds, compound 5 (2,3-dihydro-1,4-benzodioxine- 5-carboxylic acid) and compound 6 (1-acetyl-4-hydroxypyrrolidine-2-carboxylic acid) exhibited considerable inhibitory activity against MMP-13. Complementing to this study, we have also shown the gene expression levels of MMP-13 within the subtypes of colon and breast cancers classified from patients' tissue samples to provide a better understanding on which subtype of breast cancer patients would get benefited by MMP-13 inhibitors. Our current results show that compounds 5 and 6 could effectively inhibit MMP-13 and provide specific therapeutic possibilities in the treatment of inflammatory disorders and cancers. The characterization of these lead compounds would provide a better mechanistic understanding of exosite-based inhibition of MMP-13, which could overcome the challenges in the identification of other MMP catalytic domain-specific inhibitors.