Phosphoramidate-based peptidomimetic inhibitors of membrane type-1 matrix metalloproteinase

Abstract

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.

• Inhibitor
• MMP1
• MT1-MMP
• phosphoramidate

Acknowledgements

The authors extend appreciation to Jeffrey P. Jones for his guidance and generous support in the use of Schrodinger Maestro software as well as Gerhard Munske for the acquisition of high resolution mass spectrometry data.

Declaration of interest

The authors declare that they have no conflicts of interest. This work was supported in part by the National Institutes of Health (R01CA140617) including support for D.E.M. by a National Institutes of Health Biotechnology Training Grant (T32GM008336).

Supplementary material available online

Supplementary Material