Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer

ABSTRACT

Introduction: The overexpression of matrix metalloproteinase (MMP) plays an important role in the context of tumor invasion and metastasis, and MMP-2 has been characterized as the most validated target for cancer. Therefore, it is necessary to design matrix metalloproteinase inhibitors (MMPIs) that would be active and selective against MMP-2 but non-selective toward other MMPs.

Areas covered: This article clearly describes the structural character of MMP-2 followed by a review of the recent development of selective MMP-2 inhibitors based on their basic structures.

Expert opinion: Over the past 30 years, MMPs have been considered to be attractive cancer targets, and several different types of synthetic inhibitors have been identified as anticancer agents, but only a small number of small MMPIs have been examined in clinical trials, and none of these molecules has been established as anticancer drugs due to their adverse effects. One major possibility is that the MMPIs used in clinical trials were broad-spectrum drugs that also inhibited the anti-tumor effects and influenced the mediation of the normal physiological processes of MMPs. MMP-2 has recently been characterized as the most validated target for cancer. Therefore, the design and synthesis of selective MMP-2 inhibitors would be helpful for the treatment of cancer.

KEYWORDS:

• MMP-2
• inhibitor
• selective
• cancer
• tumor invasion
• metastasis

Article highlights

• Cancer is an important global health issue.

• Overexpression of matrix metalloproteinase plays an important role in tumor invasion and metastasis.

• Broad-spectrum drugs exhibited major adverse effects and failed in clinical trials.

• MMP-2 has been reported to be the most validated target.

• Selective MMP-2 inhibitors have shown promise for the prevention and treatment of cancer.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by the Natural Science Foundation of Jiangsu Province (BK20151563), the Six Talents Project Funded by Jiangsu Province (2013-YY-010), the Technology Innovation Venture Fund by Nanjing University of Chinese Medicine (CX201503), the Program for Excellent Talents in the School of Pharmacy of Nanjing University of Chinese Medicine (15ZYXET-1), a Project funded by Priority Academic Program Development of the Jiangsu Higher Education Institutions and a Project Funded by the Flagship Major Development of Jiangsu Higher Education Institutions (PPZY2015A070), and the Key Laboratory of Therapeutic Material of Chinese Medicine, Jiangsu Province, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine.