Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United States.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United States.
Adv Pharmacol. 2024;100:181-207. doi: 10.1016/bs.apha.2024.04.001. Epub 2024 Apr 24.
The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by phosphorylating a diverse collection of protein substrates consisting of other kinases, transcription factors, structural proteins, and other regulatory proteins. ERK1/2 regulation of cell functions is tightly regulated through the balance between activating phosphorylation by upstream kinases and inactivating dephosphorylation by phosphatases. Disruption of homeostatic ERK1/2 regulation caused by elevated extracellular signals or mutations in upstream regulatory proteins leads to the constitutive activation of ERK1/2 signaling and uncontrolled cell proliferation observed in many types of cancer. Many inhibitors of upstream kinase regulators of ERK1/2 have been developed and are part of targeted therapeutic options to treat a variety of cancers. However, the efficacy of these drugs in providing sustained patient responses is limited by the development of acquired resistance often involving re-activation of ERK1/2. As such, recent drug discovery efforts have focused on the direct targeting of ERK1/2. Several ATP competitive ERK1/2 inhibitors have been identified and are being tested in cancer clinical trials. One drug, Ulixertinib (BVD-523), has received FDA approval for use in the Expanded Access Program for patients with no other therapeutic options. This review provides an update on ERK1/2 inhibitors in clinical trials, their successes and limitations, and new academic drug discovery efforts to modulate ERK1/2 signaling for treating cancer and other diseases.
细胞外信号调节激酶 1 和 2（ERK1/2）是广泛调节许多细胞功能的调节剂，包括增殖、分化、迁移和细胞死亡。ERK1/2 通过磷酸化由其他激酶、转录因子、结构蛋白和其他调节蛋白组成的多样化蛋白底物来调节细胞功能。ERK1/2 对细胞功能的调节通过上游激酶的激活磷酸化和磷酸酶的失活磷酸化之间的平衡来严格控制。由于细胞外信号的升高或上游调节蛋白的突变导致 ERK1/2 信号的持续激活和许多类型癌症中观察到的不受控制的细胞增殖，导致 ERK1/2 稳态调节的破坏。已经开发出许多 ERK1/2 上游激酶调节剂的抑制剂，并作为治疗各种癌症的靶向治疗选择的一部分。然而，这些药物在提供持续的患者反应方面的疗效受到获得性耐药性的限制，这种耐药性通常涉及 ERK1/2 的重新激活。因此，最近的药物发现工作集中在 ERK1/2 的直接靶向上。已经确定了几种 ATP 竞争性 ERK1/2 抑制剂，并正在癌症临床试验中进行测试。一种药物 Ulixertinib（BVD-523）已获得 FDA 批准用于无其他治疗选择的患者的扩大准入计划。本文综述了临床试验中 ERK1/2 抑制剂的最新进展，及其成功和局限性，以及新的学术药物发现努力，以调节 ERK1/2 信号通路治疗癌症和其他疾病。
