Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy

Abstract

The extracellular signal-regulated kinase 5 (ERK5) signaling pathway is one of four conventional mitogen-activated protein (MAP) kinase pathways. Genetic perturbation of ERK5 has suggested that modulation of ERK5 activity may have therapeutic potential in cancer chemotherapy. This Miniperspective examines the evidence for ERK5 as a drug target in cancer, the structure of ERK5, and the evolution of structurally distinct chemotypes of ERK5 kinase domain inhibitors. The emerging complexities of ERK5 pharmacology are discussed, including the confounding phenomenon of paradoxical ERK5 activation by small-molecule ERK5 inhibitors. The impact of the recent development and biological evaluation of potent and selective bifunctional degraders of ERK5 and future opportunities in ERK modulation are also explored.

Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient Degraders of Extracellular Signal-Regulated Kinase 5

“…Significant recent advancements have been made in the research and development of ERK5 inhibitors. 22 However, concerns have been raised about the validity of these findings using ERK5 inhibitors, as several inhibitors may have poor selectivity and their off-target effects may produce erroneous conclusions. 23 Moreover, ERK5 inhibitors can reportedly activate the ERK5 pathway, so this danger must be considered when designing ERK5 inhibitors.…”