Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 31, Issue 1, Pages 167-171Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2015.1010528
Keywords
Inhibitor; MMP1; MT1-MMP; phosphoramidate
Funding
- National Institutes of Health [R01CA140617]
- National Institutes of Health Biotechnology Training Grant [T32GM008336]
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Membrane-type I matrix metalloproteinases (MT1-MMP) is an enzyme critical to the remodeling and homeostasis of extracellular matrix, and when over expressed it contributes to metastasis and cancer cell progression. Because of its role and implication as a biomarker that is upregulated in various cancers, MT1-MMP has become an attractive target for drug discovery. A small pilot library of peptidomimetics containing a phosphoramidate core as a zinc-binding group was synthesized and tested for inhibitory potency against MT1-MMP. From this library, a novel two residue peptidomimetic scaffold was identified that confers potency against MT1-MMP at submicromolar concentrations. The results of this study confirm that for this scaffold, valine is favored as a P1 residue and leucine in the P1 position. Furthermore, steric tolerance was observed for the N-terminus, thus implicating that a second-generation library could be constructed to extend the scaffold to P2 without concomitant loss of affinity within the MT1-MMP catalytic domain.
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