Third time lucky? Getting a grip on matrix metalloproteinases

Abstract

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.

Figure 1.

Mechanisms of MMP inhibitors. A, mode of action of initial MMPIs (yellow), which blocked the catalytic zinc ion (magenta) at the bottom of the active-site cleft (cyan). The cleft has subsites upstream (S₁, S₂, S₃,…) and downstream (S₁′, S₂′, S₃′,…) of the metal to accommodate the side chains of substrates. In MMPs, the primary specificity pocket is S₁′. B, mode of action of current small-molecule MMPIs, which mostly bind to S₁′ and/or exosites rather than the zinc. C, the chemical structure of compound JNJ0966. D, a novel approach by Scannevin et al. (9), in which the MMPI (green) targets the final activation point of the zymogen and prevents prodomain (blue) removal. This MMPI does not inhibit the mature MMP.