Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitors.
Matrix metalloproteinase (MMP)-11, or Stromelysin 3, is a particular member of MMP family, a group of zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling. Despite intense efforts since its first characterization 15 years ago, its role and target substrates in different diseases remain largely unknown. While mice with MMP-11 deficiency display no particular phenotype, analysis of different tumorigenesis models with these mice lead to the conclusion that MMP-11 promotes tumor development. In contrast with other MMPs, MMP-11 is unable to degrade any major extracellular matrix component and unlike most of other MMPs that are secreted as inactive proenzymes and activated extracellularly, MMP-11 is secreted under active form. MMP-11 may thus play a unique role in tissue remodeling processes, including those associated with tumor progression. Although MMP-11 and other MMPs have been considered as promising targets to combat cancer, a first series of clinical trials using broad-spectrum MMP inhibitors have not led to significant therapeutic benefits. These disappointing results highlight the need for better understanding of the exact role played by each MMP during the different stages of tumor progression. Among the different strategies to fill this gap, highly specific MMP inhibitors would be of great value. This review provides an update on the selectivity profile of phosphinic MMP-11 synthetic inhibitors developed and discusses the opportunities and limitations to identify inhibitors able to fully discriminate MMP-11 from the other MMPs.
Matziari
Magdalini
M
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou 15771, Athens, Greece.
Dive
Vincent
V
Yiotakis
Athanasios
A
D000818:Animals; D006801:Humans; D053507:Matrix Metalloproteinase 11 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009369:Neoplasms / Q000503:physiopathology; D009842:Oligopeptides / Q000737:chemistry; D010721:Phosphinic Acids / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*
D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D010721:Phosphinic Acids; D011480:Protease Inhibitors; C423682:RXP03; D053507:Matrix Metalloproteinase 11