title: 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.
authors: a Department of Chemistry , Washington State University , Pullman , Washington , DC , USA.
authors: Desiree E
authors: DE
authors: Mendes
authors: a Department of Chemistry , Washington State University , Pullman , Washington , DC , USA.
authors: Annie
authors: A
authors: Wong-On-Wing
authors: a Department of Chemistry , Washington State University , Pullman , Washington , DC , USA.
authors: Clifford E
authors: CE
authors: Berkman
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D057786:Peptidomimetics / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D061965:Matrix Metalloproteinase Inhibitors; D057786:Peptidomimetics; D010756:Phosphoric Acids; D011994:Recombinant Proteins; C011067:phosphoramidic acid; D053511:Matrix Metalloproteinase 14
keywords: Inhibitor; MMP1; MT1-MMP; phosphoramidate