Journal
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
Volume 80, Issue 11, Pages 2122-2131Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/09168451.2016.1200456
Keywords
collagenase-3; cancer; MMP inhibitors; hemopexin domain; exosite inhibitors
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Funding
- Department of Obstetrics and Gynecology
- National University of Singapore
- National Medical Research Council, Singapore
- Singapore Ministry of Education [R174-000-001-731]
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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.
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