Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy

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.