The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered “undruggable”, but their position as essential regulators of the MAPKs make them promising therapeutic targets. MKPs have been implicated as potential targets for cancer, cardiovascular disease, metabolic and inflammatory tissue diseases. However, successful development of highly specific, orally bioavailable small molecule inhibitors of the MKPs has not materialized. MKP5 has been implicated as a potential target for the treatment of dystrophic muscle disease through mechanisms that regulate the actions of the transforming growth factor-β (TGF-β) pathway in the development of skeletal muscle fibrosis. 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 an undescribed allosteric binding pocket in the phosphatase domain. Binding of inhibitor to this pocket collapses the MKP5 active site and is predicted to limit MAPK binding. Treatment with the inhibitor recapitulates the phenotype of MKP5-deficiency resulting in activation of p38α MAPK and JNK. Additionally, the MKP5 inhibitor blocked activation of the TGF-β pathway. The novel allosteric pocket in the phosphatase domain of MKP5 bound by the inhibitor is conserved amongst the MKPs but with discrete differences that suggest the allosteric pocket exhibits unique molecular properties specific to each MKP. As such, the MKP5 inhibitor exhibits high selectivity to MKP5 over other MKP family members. The identification of an allosteric site on MKP5 provides a strategy for small molecule inhibition of the MKPs. Furthermore, allosteric MKP5 inhibition represents a novel therapeutic strategy for the treatment of dystrophic muscle disease.

A novel allosteric site on MKP5 reveals a strategy for small molecule inhibition

ACS Fall 2021

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