Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP).
Antineoplastic Agents
/ chemical synthesis
Cell Line, Tumor
Cell Movement
/ drug effects
Collagen
/ metabolism
Drug Design
Enzyme Activation
/ drug effects
Humans
Hydroxamic Acids
/ chemical synthesis
Matrix Metalloproteinase 14
/ metabolism
Matrix Metalloproteinase Inhibitors
/ chemical synthesis
Molecular Dynamics Simulation
Molecular Structure
Protein Multimerization
/ drug effects
Sulfonamides
/ chemical synthesis
Arylsulfonamide hydroxamates
Bifunctional inhibitors
MMP inhibitors
MT1-MMP homodimerization
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 01 2019
01 01 2019
Historique:
received:
31
07
2018
revised:
27
11
2018
accepted:
28
11
2018
pubmed:
14
12
2018
medline:
18
10
2019
entrez:
8
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30522899
pii: S0968-0896(18)31373-7
doi: 10.1016/j.bmc.2018.11.041
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Hydroxamic Acids
0
Matrix Metalloproteinase Inhibitors
0
Sulfonamides
0
Collagen
9007-34-5
MMP14 protein, human
EC 3.4.24.80
Matrix Metalloproteinase 14
EC 3.4.24.80
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
196-207Subventions
Organisme : Medical Research Council
ID : G0802007
Pays : United Kingdom
Informations de copyright
Copyright © 2018 Elsevier Ltd. All rights reserved.