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Third time lucky? Getting a grip on matrix metalloproteinases

Drug candidates against matrix metalloproteinases (MMPs) failed in the clinic in the past because their strong zinc-targeting warheads led to a lack of specificity. More recently, significant selectivity among MMPs was achieved by blocking the enzymes' specificity pockets, nearby exosites, and downstream domains. Scannevin and colleagues now elegantly twist the plot and achieve ultimate selectivity: They target MMP-9 by allosterically preventing activation of its zymogen.