ERK5 kinase activity is dispensable for cellular immune response and proliferation.
Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.
ActivX Biosciences, Inc., La Jolla, CA 92037; emmel@activx.com jonr@activx.com.
Emme C K
EC
Lin
ActivX Biosciences, Inc., La Jolla, CA 92037.
Christopher M
CM
Amantea
ActivX Biosciences, Inc., La Jolla, CA 92037.
Tyzoon K
TK
Nomanbhoy
ActivX Biosciences, Inc., La Jolla, CA 92037.
Helge
H
Weissig
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi 329-0114, Japan.
Junichi
J
Ishiyama
ActivX Biosciences, Inc., La Jolla, CA 92037.
Yi
Y
Hu
ActivX Biosciences, Inc., La Jolla, CA 92037.
Shyama
S
Sidique
ActivX Biosciences, Inc., La Jolla, CA 92037.
Bei
B
Li
ActivX Biosciences, Inc., La Jolla, CA 92037.
John W
JW
Kozarich
ActivX Biosciences, Inc., La Jolla, CA 92037; emmel@activx.com jonr@activx.com.
Jonathan S
JS
Rosenblum
D000818:Animals; D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059467:Transcriptome
D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D048054:Mitogen-Activated Protein Kinase 7
ERK5; bromodomain; inflammation; kinase; proliferation
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