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Design,synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP)
Authors:Doretta Cuffaro  Elisa Nuti  Valentina Gifford  Noriko Ito  Caterina Camodeca  Tiziano Tuccinardi  Susanna Nencetti  Elisabetta Orlandini  Yoshifumi Itoh  Armando Rossello
Institution: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
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.
Keywords:MT1-MMP homodimerization  Bifunctional inhibitors  Arylsulfonamide hydroxamates  MMP inhibitors
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