title: Functional characterization of selective exosite-binding inhibitors of matrix metalloproteinase-13 (MMP-13) - experimental validation in human breast and colon cancer.
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.
authors.affiliation: a Department of Obstetrics and Gynecology , National University of Singapore , Singapore.
authors.forename: Roopa
authors.initials: R
authors.lastname: Kothapalli
authors.affiliation: b Department of Pharmacology , National University of Singapore , Singapore.
authors.forename: Kodappully
authors.initials: K
authors.lastname: Sivaraman Siveen
authors.affiliation: c Cancer Science Institute of Singapore, National University of Singapore , Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: c Cancer Science Institute of Singapore, National University of Singapore , Singapore.|d Department of Biochemistry , National University of Singapore , Singapore.|e Institute of Molecular and Cellular Biology , Proteos 6-03 , Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: b Department of Pharmacology , National University of Singapore , Singapore.|c Cancer Science Institute of Singapore, National University of Singapore , Singapore.|f School of Biomedical Sciences , Curtin University , Bentley , Australia.|g Department of Biological Sciences , University of North Texas , Denton , TX , USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: b Department of Pharmacology , National University of Singapore , Singapore.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: h Department of Biological Sciences , National University of Singapore , Singapore.
authors.forename: Kunchithapadam
authors.initials: K
authors.lastname: Swaminathan
keywords: MMP inhibitors; cancer; collagenase-3; exosite inhibitors; hemopexin domain