Design,synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
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Authors: | Doretta Cuffaro Elisa Nuti Valentina Gifford Noriko Ito Caterina Camodeca Tiziano Tuccinardi Susanna Nencetti Elisabetta Orlandini Yoshifumi Itoh Armando Rossello |
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Affiliation: | 1. Department of Pharmacy, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy;2. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom;3. Department of Earth Sciences, University of Pisa, Via Santa Maria 53, 56126 Pisa, Italy |
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Abstract: | 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. |
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Keywords: | MT1-MMP homodimerization Bifunctional inhibitors Arylsulfonamide hydroxamates MMP inhibitors |
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