The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma

Abstract

The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became clear that initial MMP inhibitor clinical trials were held prematurely. Further complicating matters were problematic conclusions drawn from animal model studies. The most recent generation of MMP inhibitors have desirable selectivities and improved pharmacokinetics, resulting in improved toxicity profiles. Application of selective MMP inhibitors led to the conclusion that MMP-2, MMP-9, MMP-13, and MT1-MMP are not involved in musculoskeletal syndrome, a common side effect observed with broad spectrum MMP inhibitors. Specific activities within a single MMP can now be inhibited. Better definition of the roles of MMPs in immunological responses and inflammation will help inform clinic trials, and multiple studies indicate that modulating MMP activity can improve immunotherapy. There is a U.S. Food and Drug Administration (FDA)-approved MMP inhibitor for periodontal disease, and several MMP inhibitors are in clinic trials, targeting a variety of maladies including gastric cancer, diabetic foot ulcers, and multiple sclerosis. It is clearly time to move on from the dogma of viewing MMP inhibition as intractable.

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

“…Although broad spectrum MMP inhibitors limit PDAC progression in preclinical animal models [73][74][75][76][77][78][79][80][81][82], they seem to lack efficacy in a clinical setting [115,116]. This disparity between preclinical data and clinical trials can be attributed to several factors-for instance, differences in pharmacokinetics, pharmacodynamics and metabolism and the failure to accurately model the tumor microenvironment [128].…”

“…The fact that there are no clinical benefits obtained through MMP inhibition does not imply that MMPs do not contribute to PDAC progression. As elegantly discussed [116,117], the disappointing clinical trial results may be due to several reasons, of which the inclusion of advanced stage disease seems most relevant. Broad spectrum MMP inhibitors may also lack efficacy as they could block the potential tumor inhibitory activities of specific MMPs.…”

Matrix Metalloproteinases and Glaucoma Treatment

“…Role of MMPs in physiologic (A) and pathologic conditions (B). 2,8,19,112 MMP, matrix metalloproteinase. CA-MMP, cysteine array MMP; CXCL5, chemokine (C-X-C motif) ligand 5; ECM, extracellular matrix; FGF-R1, fibroblast growth factor receptor 1; IGF-BP, insulin-like growth factor binding protein; IL, interleukin; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; PMNL, polymorphonuclear leukocytes; pro-HB-EGF, pro-heparin-binding epidermal growth factor-like growth factor; RASI-1, rheumatoid arthritis synovium inflamed-1; SDF-1, stromal cell-derived factor 1; TGF, transforming growth factor; TNF, tumor necrosis factor; VSM, vascular smooth muscle.…”

“…17,18 MMP inhibition also has been proposed as a therapeutic approach for diabetic foot ulcers and currently is utilized in the treatment of periodontal disease. 19 In contrast, PGAs that increase MMP activity have proven to be useful in the treatment of glaucoma. Glaucoma is treated by lowering IOP, and increasing MMP activity in target intraocular tissues for IOP lowering causes ECM remodeling that results in a decrease in IOP.…”

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

“…As such, there is a current resurgence in research focused on the use of MMP inhibitors. With improved strategies for targeting MMPs, recent studies have shown favorable anti-tumorigenic phenotypes in in vitro and in vivo studies, which have progressed to clinical trials (34, 35).…”