TY - JOUR T1 - ERK5 kinase activity is not required for cellular immune response JF - bioRxiv DO - 10.1101/038513 SP - 038513 AU - Emme C.K. Lin AU - Christopher M. Amantea AU - Tyzoon K. Nomanbhoy AU - Helge Weissig AU - Junichi Ishiyama AU - Yi Hu AU - Shyama Sidique AU - Bei Li AU - John W. Kozarich AU - Jonathan S. Rosenblum Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/02/01/038513.abstract N2 - Extracellular signal-regulated protein kinase 5 (ERK5) has been associated with several pathological states including cancer, cardiac hypertrophy, and inflammation. Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability. Pharmacological inhibition of ERK5 with XMD8-92, a first generation ERK5 inhibitor, is efficacious in various oncology and inflammation models. Here we report the synthesis and characterization of potent and selective ERK5 inhibitors. Most of these compounds displayed good efficacy in cellular inflammation assays; intriguingly, other compounds lacked efficacy despite potently inhibiting ERK5 in vivo. The source of XMD8-92 and related compounds’ efficacy is now demonstrated to be from direct inhibition of bromodomains (BRDs), conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. We found no cellular effect from pure ERK5 inhibitors and conclude that ERK5 kinase activity is not required for the immune response. The role of ERK5 in inflammation and oncology should be reinvestigated. ER -