Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge.

Article Details


Georgiadis D, Yiotakis A

Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge.

Bioorg Med Chem. 2008 Oct 1;16(19):8781-94. doi: 10.1016/j.bmc.2008.08.058. Epub 2008 Aug 29.

PubMed ID
18790648 [ View in PubMed

Zn-metalloproteinases are an important class of hydrolytic enzymes that are characterized by the presence of a catalytic zinc(II) atom in their active center which is fundamental for proteolytic activity. Metzincins, a superfamily of Zn-metalloproteinases with many structural and functional commonalities among its members, are responsible for the fine tuning of key physiological functions in mammals and the deregulation of their activity is directly connected to numerous inflammatory and degenerative diseases such as arthritis or cancer. Development of small-molecule exogenous inhibitors of metzincins able to re-establish normal proteolytic activity in pathological conditions has been a field of intense research effort for many years but applications in the clinic were not always successful. One of the main reasons for this failure is the uncontrolled action of these inhibitors on target as well as anti-target metzincin family members. Current medicinal efforts have been shifted to the discovery of target-specific inhibitors that will help to improve our understanding of metzincins biological function and provide the basis for the development of safer pharmaceutical agents. This review focuses on the cases of certain medicinally important metzincins [matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), ADAMs with thrombospondin motifs (ADAMTSs), and procollagen C-proteinase (PCP)] and summarizes the latest advances on the discovery of inhibitors of these enzymes that display improved selectivity profiles.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-{[4-(but-2-yn-1-yloxy)phenyl]sulfonyl}propane-1-thiolDisintegrin and metalloproteinase domain-containing protein 17Ki (nM)10N/AN/ADetails
methyl (1R,2S)-2-(hydroxycarbamoyl)-1-{4-[(2-methylquinolin-4-yl)methoxy]benzyl}cyclopropanecarboxylateDisintegrin and metalloproteinase domain-containing protein 17Ki (nM)8N/AN/ADetails
PF-00356231Macrophage metalloelastaseIC 50 (nM)14N/AN/ADetails