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Collagen degradation and proMMP-2 activation are major functions of MT1-MMP to promote cancer cell invasion. Since both processes require MT1-MMP homodimerization on the cell surface, herein we propose that the use of bifunctional inhibitors of this enzyme could represent an innovative approach to efficiently reduce tumor growth. A small series of symmetrical dimers derived from previously described monomeric arylsulfonamide hydroxamates was synthesized and tested in vitro on isolated MMPs. A nanomolar MT1-MMP inhibitor, compound 6, was identified and then submitted to cell-based assays on HT1080 fibrosarcoma cells. Dimer 6 reduced MT1-MMP-dependent proMMP-2 activation, collagen degradation and collagen invasion in a dose-dependent manner with better results even compared to its monomeric analogue 4. This preliminary study suggests that dimeric MT1-MMP inhibitors might be further developed and exploited as an alternative tool to reduce cancer cell invasion.

Original publication




Journal article


Bioorg Med Chem

Publication Date





196 - 207


Arylsulfonamide hydroxamates, Bifunctional inhibitors, MMP inhibitors, MT1-MMP homodimerization, Antineoplastic Agents, Cell Line, Tumor, Cell Movement, Collagen, Drug Design, Enzyme Activation, Humans, Hydroxamic Acids, Matrix Metalloproteinase 14, Matrix Metalloproteinase Inhibitors, Molecular Dynamics Simulation, Molecular Structure, Protein Multimerization, Sulfonamides