Functional characterization of selective exosite-binding inhibitors of matrix metalloproteinase-13 (MMP-13) – experimental validation in human breast and colon cancer. Issue 11 (1st November 2016)

• Record Type: Journal Article
• Authors: Kothapalli, Roopa; Sivaraman Siveen, Kodappully; Tan, Tuan Zea; Thiery, Jean Paul; Kumar, Alan Prem; Sethi, Gautam; Swaminathan, Kunchithapadam
• Is Part Of: Bioscience, biotechnology, and biochemistry. Volume 80:Issue 11(2016)
• Page Start: 2122
• Page End: 2131
• Publication Date: 2016-11-01
• Subjects: collagenase-3 -- cancer -- MMP inhibitors -- hemopexin domain -- exosite inhibitors; Biotechnology -- Periodicals; Biochemistry -- Periodicals; 660.6
• DOI: 10.1080/09168451.2016.1200456
• Languages: English
• ISSNs: 0916-8451

Abstract

Abstract: 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. Graphical abstract: : Exosite inhibition of matrix metalloproteinase-13.