Challenges with matrix metalloproteinase inhibition and future drug discovery avenues

ABSTRACT

Introduction

Matrix metalloproteinases have been in the scope of pharmaceutical drug discovery for decades as promising targets for drug development. Until present, no modulator of the enzyme class survived clinical trials, all failing for various reasons. Nevertheless, the target family did not lose its attractiveness and there is ever more evidence that MMP modulators are likely to overcome the hurdles and result in successful clinical therapies.

Areas Covered

This review provides an overview of past efforts that were taken in the development of MMP inhibitors and insight into promising strategies that might enable drug discovery in the field in the future. Small molecule inhibitors as well as biomolecules are reviewed.

Expert opinion

Despite the lack of successful clinical trials in the past, there is ongoing research in the field of MMP modulation, proving the target class has not lost its appeal to pharmaceutical research. With ever-growing insights from different scientific fields that shed light on previously unknown correlations, it is now time to use synergies deriving from biological knowledge, chemical structure generation, and clinical application to reach the ultimate goal of bringing MMP derived drugs on a broad front for the benefit of patients into therapeutic use.

KEYWORDS:

• Antibodies
• drug design
• drug discovery
• hemopexin-like domain
• matrix metalloproteinase
• medicinal chemistry
• polypharmacology
• small-molecule inhibitors

Article Highlights

• Matrix metalloproteinases attract pharmaceutical researchers for decades already, while we are still waiting for a successful MMP derived therapeutic treatment.

• Small molecules as well as antibodies, or fragments thereof, have been investigated with respect to beneficially influence the MMP microenvironment.

• For both approaches, small molecule inhibitors and inhibitory antibodies, examples are presented.

• Most MMP modulators inhibit the catalytic function of one or several members of the enzyme class, while there is evidence that other domains might be more attractive target sites.

• Novel approaches of interfering with the MMP network are highlighted.

• Future avenues are outlined that might lead to the next generation of MMP modulators that finally succeed in clinical trials.

Declaration of Interest

The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

One referee is an employee of MMP Biopharma. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by the Zurich University of Applied Sciences via a Start-up fund (AS-2020-1).