Targeting mitogen-activated protein kinase phosphatase-1 (MKP-1): structure-based design of MKP-1 inhibitors and upregulators.
Mitogen-activated protein kinase phosphatases (MKPs) are dual specificity protein phosphatases (DUSPs) that dephosphorylate both phospho-tyrosine and phospho-threonine residues on mitogen-activated protein kinases (MAPKs). Because the MAPK family of signalling molecules (phospho-p38 MAPK, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)) play essential roles in cell signalling pathways that regulate cell growth and inflammation, controlling MAPK-mediated pathways is a therapeutically attractive strategy. While small molecule MAPK inhibitors have utility, in this review we will focus on exploring the potential of targeting the endogenous MAPK deactivator--MKP-1. Importantly, there is a strong justification for developing both inhibitors and upregulators of MKP-1 because of the diverse roles played by MAPKs in disease: for example, in cancer, MKP-1 inhibitors may prove beneficial, as MKP-1 is overexpressed and is considered responsible for the failure of JNK-driven apoptotic pathways induced by chemotherapeutics; conversely, in inflammatory diseases such as asthma and arthritis, MKP-1 reduces MAPK-mediated signalling and developing novel ligands to upregulate MKP-1 levels would be a therapeutically attractive anti-inflammatory strategy. Thus, in this review we utilise MKP-1 homology modeling to highlight the structural features of MKP-1 inhibitors that permit potent and selective inhibition, and to provide insights into the structural requirements for selective MKP-1 upregulators.
Faculty of Pharmacy, University of Sydney, NSW 2006 Australia.
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MR
Doddareddy
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Rawling
A J
AJ
Ammit
D001665:Binding Sites; D003198:Computer Simulation; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D004791:Enzyme Inhibitors; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases