LAUSR

ERK5 (Extracellular signal regulated kinase 5, also known as MAPK7, Gene ID: 5598) is a key integrator of cellular signal transduction and it has been shown to play a role in various cellular processes such as proliferation, differentiation, apoptosis and cell survival. Several studies have demonstrated that inhibition of ERK5 with siRNA or shRNA decreases proliferation and increases cell death in different tumor models, thereby highlighting the potential of ERK5 as a therapeutic target in cancer. By HTS and subsequent lead identification, we discovered a highly potent and selective ERK5 inhibitor, BAY-885, which was used to investigate the therapeutic potential of ERK5 in tumor cells displaying ERK5 genomic amplifications or with constitutive activation of the ERK5 pathway. BAY-885 inhibited ERK5 enzymatic activity with IC50 = 40 nM and was highly selective vs. 357 kinases (Eurofins panel). Inhibition by BAY-855 was confirmed in a cellular setting using a MEF2 reporter cell line (SN12C-MEF2-luc). The EGF-stimulated MEF2 transcriptional activity was strongly inhibited by BAY-885 (IC50 = 115 nM; IC90 = 691 nM). In contrast, the compound had no effect on a reporter cell line with constitutive luciferase expression (SN12C-CMV-luc, IC50 > 50 µM), thereby ruling out potential effects as a general inhibitor of transcription or translation. Importantly, despite its high potency, BAY-885 failed to inhibit the proliferation of cells with ERK5 genomic amplification (SN12C, SNU-449, MFM-223) or with constitutively active ERK5 signaling (BT-474, SK-BR-3). Altogether, our results demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, thus raising doubts as to the viability of ERK5 as a therapeutic target for anticancer drug development. The availability of potent and selective chemical probes, as the one described here, will contribute to further understanding the biology of ERK5 signaling in cancer. Citation Format: Clara Lemos, Duy Nguyen, Lars Wortmann, Ulf Bomer, Simon Holton, Christian Lechner, Stefan Prechtl, Detlev Sulzle, Franziska Siegel, Dominik Mumberg, Marcus Bauser, Andrea Hagebarth. Discovery and profiling of a highly potent and selective ERK5 inhibitor: BAY-885 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5866.