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.

细胞外信号调节激酶5（extracellular signal-regulated kinase 5，ERK5）信号通路是四种经典丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）通路之一。针对ERK5的遗传扰动研究表明，调控其活性或可在癌症化疗中展现治疗潜力。本迷你综述（Miniperspective）系统梳理了ERK5作为癌症治疗药物靶点的相关证据、ERK5的蛋白结构，以及ERK5激酶结构域抑制剂的不同结构类型化学骨架的发展脉络。文中还探讨了ERK5药理学研究中逐渐显现的复杂问题，包括小分子ERK5抑制剂诱导ERK5产生悖论性激活这一令人困惑的混杂现象。此外，本文亦探讨了强效且具有高选择性的ERK5双功能降解剂的最新研发进展与生物学评价，以及ERK调控领域的未来研究机遇。