Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge.
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.
Georgiadis
Dimitris
D
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou 15771, Athens, Greece. dgeorgia@chem.uoa.gr
Yiotakis
Athanasios
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D055395:Bone Morphogenetic Protein 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D019699:Thrombospondins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D061965:Matrix Metalloproteinase Inhibitors; D019699:Thrombospondins; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D055395:Bone Morphogenetic Protein 1; D000072198:ADAM17 Protein; D015032:Zinc