ERK5 活性调节作为一种治疗癌症的策略。
Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy.
机构信息
Cancer Research Horizons Therapeutic Innovation, Newcastle Drug Discovery Group, Newcastle University Centre for Cancer, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, United Kingdom.
Cancer Research Horizons Therapeutic Innovation, Newcastle Drug Discovery Group, Translational and Clinical Research Institute, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom.
出版信息
J Med Chem. 2023 Apr 13;66(7):4491-4502. doi: 10.1021/acs.jmedchem.3c00072. Epub 2023 Apr 1.
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（ERK5）信号通路是四条传统的有丝分裂原激活蛋白（MAP）激酶通路之一。ERK5 的遗传扰动表明，ERK5 活性的调节可能在癌症化疗中有治疗潜力。本专论考察了 ERK5 作为癌症药物靶点的证据、ERK5 的结构以及结构上不同的 ERK5 激酶结构域抑制剂的化学型的演变。讨论了 ERK5 药理学的新兴复杂性，包括小分子 ERK5 抑制剂引起的矛盾性 ERK5 激活的混淆现象。还探讨了最近强效和选择性 ERK5 双功能降解物的开发和生物学评估以及 ERK 调节的未来机会的影响。
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