Identification of pharmacological inhibitors of the MEK5/ERK5 pathway

We have identified two novel MEK5 inhibitors, BIX02188 and BIX02189, which inhibited catalytic function of purified, MEK5 enzyme. The MEK5 inhibitors blocked phosphorylation of ERK5, without affecting phosphorylation of ERK1/2 in sorbitol-stimulated HeLa cells. The compounds also inhibited transcrip...

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Veröffentlicht in:	Biochemical and biophysical research communications 2008-12, Vol.377 (1), p.120-125
Hauptverfasser:	Tatake, Revati J., O’Neill, Margaret M., Kennedy, Charles A., Wayne, Anita L., Jakes, Scott, Wu, Di, Kugler, Stanley Z., Kashem, Mohammed A., Kaplita, Paul, Snow, Roger J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Aniline Compounds - isolation & purification Aniline Compounds - pharmacology ERK5 HeLa Cells Humans Indoles - isolation & purification Indoles - pharmacology Kinase inhibitors MADS Domain Proteins - antagonists & inhibitors MADS Domain Proteins - genetics MAP Kinase Kinase 5 - antagonists & inhibitors MAP Kinase Kinase 5 - metabolism MEF2 Transcription Factors MEK5 Mitogen-Activated Protein Kinase 7 - antagonists & inhibitors Mitogen-Activated Protein Kinase 7 - metabolism Myogenic Regulatory Factors - antagonists & inhibitors Myogenic Regulatory Factors - genetics Pharmacological inhibitors Phosphorylation - drug effects Protein Kinase Inhibitors - isolation & purification Protein Kinase Inhibitors - pharmacology Sorbitol - pharmacology Transcriptional Activation - drug effects
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Zusammenfassung:	We have identified two novel MEK5 inhibitors, BIX02188 and BIX02189, which inhibited catalytic function of purified, MEK5 enzyme. The MEK5 inhibitors blocked phosphorylation of ERK5, without affecting phosphorylation of ERK1/2 in sorbitol-stimulated HeLa cells. The compounds also inhibited transcriptional activation of MEF2C, a downstream substrate of the MEK5/ERK5 signaling cascade, in a cellular trans-reporter assay system. These inhibitors offer novel pharmacological tools to better characterize the role of the MEK5/ERK5 pathway in various biological systems.
ISSN:	0006-291X 1090-2104
DOI:	10.1016/j.bbrc.2008.09.087