RT Journal Article SR Electronic T1 Reinvestigating the role of ERK5: kinase activity is not required for cellular immune response or proliferation JF bioRxiv FD Cold Spring Harbor Laboratory SP 038513 DO 10.1101/038513 A1 Emme C.K. Lin A1 Christopher M. Amantea A1 Tyzoon K. Nomanbhoy A1 Helge Weissig A1 Junichi Ishiyama A1 Yi Hu A1 Shyama Sidique A1 Bei Li A1 John W. Kozarich A1 Jonathan S. Rosenblum YR 2016 UL http://biorxiv.org/content/early/2016/07/26/038513.abstract AB 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 anti-inflammatory and anti-tumorigenic. 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 anti-inflammatory or anti-proliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains (BRDs), 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 non-catalytic 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.