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 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.
Department of Cardiovascular Disease, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT 06877, USA.
Revati J
RJ
Tatake
Margaret M
MM
O'Neill
Charles A
CA
Kennedy
Anita L
AL
Wayne
Scott
S
Jakes
Di
D
Wu
Stanley Z
SZ
Kugler
Mohammed A
MA
Kashem
Paul
P
Kaplita
Roger J
RJ
Snow
D000814:Aniline Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000302:isolation & purification / Q000494:pharmacology*; D026161:MADS Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D048671:MAP Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064326:MEF2 Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D013012:Sorbitol / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
D000814:Aniline Compounds; C533206:BIX 02188; C533207:BIX 02189; D007211:Indoles; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D047428:Protein Kinase Inhibitors; D013012:Sorbitol; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5