Targeting mitogen-activated protein kinase phosphatase-1 (MKP-1): Structure-based design of MKP-1 inhibitors and upregulators

Doddareddy, MR; Rawling, T; Ammit, AJ

Targeting mitogen-activated protein kinase phosphatase-1 (MKP-1): Structure-based design of MKP-1 inhibitors and upregulators

Doddareddy, MR Rawling, T

Ammit, AJ

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Publication Type:: Journal Article
Citation:: Current Medicinal Chemistry, 2012, 19 (2), pp. 163 - 173
Issue Date:: 2012-01-01

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Field	Value	Language
dc.contributor.author	Doddareddy, MR	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.available	2011-10-27	en_US
dc.date.issued	2012-01-01	en_US
dc.identifier.citation	Current Medicinal Chemistry, 2012, 19 (2), pp. 163 - 173	en_US
dc.identifier.issn	0929-8673	en_US
dc.identifier.uri	http://hdl.handle.net/10453/29009
dc.description.abstract	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 MAPKmediated 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. © 2012 Bentham Science Publishers.	en_US
dc.relation.ispartof	Current Medicinal Chemistry	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Enzyme Inhibitors	en_US
dc.subject.mesh	Up-Regulation	en_US
dc.subject.mesh	Binding Sites	en_US
dc.subject.mesh	Enzyme Activation	en_US
dc.subject.mesh	Protein Structure, Tertiary	en_US
dc.subject.mesh	Computer Simulation	en_US
dc.subject.mesh	Protein Tyrosine Phosphatases	en_US
dc.subject.mesh	Dual Specificity Phosphatase 1	en_US
dc.title	Targeting mitogen-activated protein kinase phosphatase-1 (MKP-1): Structure-based design of MKP-1 inhibitors and upregulators	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	19	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	19	en_US

Abstract:

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 MAPKmediated 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. © 2012 Bentham Science Publishers.

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http://hdl.handle.net/10453/29009