Mechanisms of Action of Novel Drugs Targeting Angiogenesis-Promoting Matrix Metalloproteinases.

Gregg B Fields

doi:10.3389/fimmu.2019.01278

Abstract

Angiogenesis is facilitated by the proteolytic activities of members of the matrix metalloproteinase (MMP) family. More specifically, MMP-9 and MT1-MMP directly regulate angiogenesis, while several studies indicate a role for MMP-2 as well. The correlation of MMP activity to tumor angiogenesis has instigated numerous drug development programs. However, broad-based and Zn2+-chelating MMP inhibitors have fared poorly in the clinic. Selective MMP inhibition by antibodies, biologicals, and small molecules has utilized unique modes of action, such as (a) binding to protease secondary binding sites (exosites), (b) allosterically blocking the protease active site, or (c) preventing proMMP activation. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages. The mechanistically non-traditional MMP inhibitors offer treatment strategies for tumor angiogenesis that avoid the off-target toxicities and lack of specificity that plagued Zn2+-chelating inhibitors.

Highlights

During the process of angiogenesis, the extracellular matrix (ECM) is degraded by matrix metalloproteinases (MMPs), facilitating endothelial cell invasion and leading to sprouting of new vessels [1,2,3]
MMP-9 and MT1-MMP directly regulate angiogenesis, while some studies indicate a role for MMP-2 as well [1, 4]
Tumor angiogenesis and growth is reduced in MMP-2 knockout mice [1]

Summary

INTRODUCTION

During the process of angiogenesis (the development of new blood vessels), the extracellular matrix (ECM) is degraded by matrix metalloproteinases (MMPs), facilitating endothelial cell invasion and leading to sprouting of new vessels [1,2,3]. The MMP family (Figure 1) has fairly conserved sequences between species, indicating that they are part of essential biological processes. The domain organization of MMPs is fairly conserved, as all contain a signal peptide, a pro-domain, and a catalytic (CAT) domain with a Zn2+ binding His-Glu-X-X-His-X-X-Gly-X-X-His motif (Figure 1). The roles of MMP-9 in angiogenesis include the release of vascular endothelial growth factor (VEGF) and/or basic fibroblast growth factor (FGF-2) [5, 7]. Tumor-associated macrophages, once polarized into the M2 phenotype, release VEGF and MMP-9 [9]. MT1MMP contributes to blood vessel invasion, FGF-2-induced corneal angiogenesis, endothelial cell

Targeting Angiogenesis

CRITICAL OVERVIEW