Matrix metalloproteinase protein inhibitors: highlighting a new beginning for metalloproteinases in medicine

Abstract:

The development of therapeutic matrix metalloproteinase (MMP) inhibitors has evolved from broad-spectrum peptidomimetic inhibitors with deleterious side effects, to highly selective agents. These range from small molecules to antibodies, antisense inhibitors, and engineered N-terminal tissue inhibitors of metalloproteinase domain. The advances in inhibitor design along with promising new global molecular insights into MMP structures, the protease web, and the role of extracellular matrix in diseases have contributed toward a renewed interest in using MMPs as valid drug targets. This review aims to address the advances and challenges concerning the design, development, and current status of anti-MMP agents in this new era of post-broad-spectrum MMP inhibitors. Highly selective inhibitors of MMPs promise to usher in an era of specific targeting of diseased tissue proteolysis networks, with markedly reduced negative repercussions, and to uncover the molecular and mechanistic roles of MMP isoforms in cancer, inflammation, and infection.

Keywords::

• matrix metalloproteinase inhibitors
• MMPI
• small molecules
• MMP-inhibiting monoclonal antibodies
• engineered N-TIMP
• miRNA

Acknowledgments

IS is supported by the Israel Science Foundation, Rising Tides Foundation, Memorial Sloan Kettering Cancer Center-Weizmann Fund, the Thompson Foundation, and the Kimmelman Center at the Weizmann Institute of Science. NP is supported by the Prostate Cancer Foundation, Friends for an Earlier Breast Cancer Test Fund, Israel Cancer Research Fund, European Research Council (ERC), Israel Science Foundation, and the DKFZ-MOST cooperation in Cancer Research Fund.

Disclosure

The authors report no conflicts of interest in this work.