Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP)
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 e...
| Huvudupphovsmän: | , , , , , , , , , |
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| Materialtyp: | Journal article |
| Språk: | English |
| Publicerad: |
Elsevier
2018
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| _version_ | 1826257118323277824 |
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| author | Cuffaro, D Nuti, E Gifford, V Ito, N Camodeca, C Tuccinardi, T Nencetti, S Orlandini, E Itoh, Y Rossello, A |
| author_facet | Cuffaro, D Nuti, E Gifford, V Ito, N Camodeca, C Tuccinardi, T Nencetti, S Orlandini, E Itoh, Y Rossello, A |
| author_sort | Cuffaro, D |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:13:03Z |
| format | Journal article |
| id | oxford-uuid:03ad4f23-841c-4757-9673-d819f65a68b4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:13:03Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:03ad4f23-841c-4757-9673-d819f65a68b42022-03-26T08:47:39ZDesign, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP)Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:03ad4f23-841c-4757-9673-d819f65a68b4EnglishSymplectic Elements at OxfordElsevier2018Cuffaro, DNuti, EGifford, VIto, NCamodeca, CTuccinardi, TNencetti, SOrlandini, EItoh, YRossello, ACollagen 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. |
| spellingShingle | Cuffaro, D Nuti, E Gifford, V Ito, N Camodeca, C Tuccinardi, T Nencetti, S Orlandini, E Itoh, Y Rossello, A Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
| title | Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
| title_full | Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
| title_fullStr | Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
| title_full_unstemmed | Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
| title_short | Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP) |
| title_sort | design synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase mt1 mmp |
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