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The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma

1
Institute for Human Health & Disease Intervention, Department of Chemistry & Biochemistry, and the Center for Molecular Biology & Biotechnology, Florida Atlantic University, Jupiter, FL 33458, USA
2
Department of Chemistry, The Scripps Research Institute/Scripps Florida, Jupiter, FL 33458, USA
Cells 2019, 8(9), 984; https://doi.org/10.3390/cells8090984
Received: 2 August 2019 / Revised: 22 August 2019 / Accepted: 26 August 2019 / Published: 27 August 2019
(This article belongs to the Special Issue Matrix Metalloproteinases: From Structure to Function)
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. View Full-Text
Keywords: matrix metalloproteinase; protease inhibitor; cancer; arthritis; wound healing matrix metalloproteinase; protease inhibitor; cancer; arthritis; wound healing
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Fields, G.B. The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma. Cells 2019, 8, 984.

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