Targeting protein serine/threonine phosphatases for drug development

Abstract

With the recent clinical success of drugs targeting protein kinase activity, drug discovery efforts are focusing on the role of reversible protein phosphorylation in disease states. The activity of protein phosphatases, enzymes that oppose protein kinases, can also be manipulated to alter cellular signaling for therapeutic benefits. In this review, we present protein serine/threonine phosphatases as viable therapeutic targets, discussing past successes, current challenges, and future strategies for modulating phosphatase activity.

Fig. 1.

Consequences of the targeted disruption of select phosphatase complexes. A to C, phosphatase complexes that can be disrupted by small molecules. The PP2A-βArr2-Akt complex (C), which is essential for dopaminergic signaling, can be disrupted by lithium salts. [Adapted from Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, and Caron MG (2008) A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 132:125-136. Copyright © 2008 Elsevier. Used with permission.] D, a phosphatase complex that could potentially be targeted for therapeutic disruption. See text for further discussion of A, B, and D.