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Drugging an “undruggable” phosphatase
The MAPK family of kinases regulates diverse physiological and pathophysiological processes and is inactivated by MAPK phosphatases including MKP5. Blocking MKP5 activity has emerged as a potential treatment for dystrophic muscle disease. Gannam et al. identified and characterized a small molecule that inhibited MKP5 by binding to an allosteric site on the phosphatase but that did not affect the activity of other related phosphatases. In muscle cells, the inhibitor blocked MKP5 from inactivating the MAPKs and inhibited the TGF-β signaling pathway that results in fibrosis in dystrophic muscle disease. These results demonstrate that it is possible to allosterically target MAPK phosphatases with a high degree of specificity, opening avenues for the treatment of diseases for which MAPK phosphatase inhibition confers therapeutic benefit.
Abstract
The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered “undruggable,” but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of dystrophic muscle disease. Here, we identified an inhibitor of MKP5 using a p38α MAPK–derived, phosphopeptide-based small-molecule screen. We solved the structure of MKP5 in complex with this inhibitor, which revealed a previously undescribed allosteric binding pocket. Binding of the inhibitor to this pocket collapsed the MKP5 active site and was predicted to limit MAPK binding. Treatment with the inhibitor recapitulated the phenotype of MKP5 deficiency, resulting in activation of p38 MAPK and JNK. We demonstrated that MKP5 was required for TGF-β1 signaling in muscle and that the inhibitor blocked TGF-β1–mediated Smad2 phosphorylation. TGF-β1 pathway antagonism has been proposed for the treatment of dystrophic muscle disease. Thus, allosteric inhibition of MKP5 represents a therapeutic strategy against dystrophic muscle disease.
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