细胞外信号调节激酶5(ERK5)信号通路是四个常规的有丝分裂原活化蛋白(MAP)激酶通路之一。对ERK5的遗传破坏表明，调节ERK5活性可能具有癌症化疗的治疗潜力。本文概述了ERK5作为癌症药物靶点的证据、ERK5的结构以及ERK5激酶结构不同的化合物类别的演化。文中还讨论了ERK5药理学的新问题，包括小分子ERK5抑制剂致使ERK5激活的波动现象。本文评估了最新发展的具有强效和选择性的双功能ERK5蛋白降解剂的生物活性和未来ERK调节的机会。

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.