Development of a Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-7/-13 Inhibitor.

Thomas Fischer,Rainer Riedl

doi:10.3390/molecules22091548

Abstract

Matrix metalloproteinase 7 (MMP-7) is a member of the MMP superfamily and is able to degrade extracellular matrix proteins such as casein, gelatin, fibronectin and proteoglycan. MMP-7 is a validated target for the development of small molecule drugs against cancer. MMP-13 is within the enzyme class the most efficient contributor to type II collagen degeneration and is a validated target in arthritis and cancer. We have developed the dual MMP-7/-13 inhibitor ZHAWOC6941 with IC50-values of 2.2 μM (MMP-7) and 1.2 μM (MMP-13) that is selective over a broad range of MMP isoforms. It spares MMP-1, -2, -3, -8, -9, -12 and -14, making it a valuable modulator for targeted polypharmacology approaches.

Highlights

Matrix metalloproteinases (MMPs) are a family of calcium- and zinc-dependent endopeptidases able to metabolize components of the extracellular matrix (ECM) [1]
We present an approach that enabled us to modify the characteristics of the MMP-13 inhibitor we Matrix metalloproteinase 7 (MMP-7)/-13 inhibitor, while conserving the selectivity profileofover
ResultsHerein, we present an approach that enabled us to modify the characteristics of the MMP-13

Summary

Introduction

Matrix metalloproteinases (MMPs) are a family of calcium- and zinc-dependent endopeptidases able to metabolize components of the extracellular matrix (ECM) [1]. The activity of MMPs is strongly regulated by the tissue inhibitors of metalloproteinases (TIMPs) [2] An imbalance in this network can lead to a series of serious diseases including, but not exclusively, different forms of cancer or arthritis [3,4,5,6,7,8]. Inhibitors of the target family incorporated a hydroxamic acid moiety as a strong metal chelating group interacting with the catalytic zinc which is conserved in all MMP isoforms [22]. This led to potent inhibitors, which did not display satisfying selectivity profiles [23]. For example MMP-13, the key player in collagen degradation and a valid target for arthritis and cancer [7,26], can be inhibited selectively and with high affinity with a variety of ligands [27,28,29]

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