State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
J Med Chem. 2020 Apr 23;63(8):3976-3995. doi: 10.1021/acs.jmedchem.9b01896. Epub 2020 Mar 5.
ERK1 and ERK5 are proposed to have pivotal roles in several types of cancer. Under some circumstance, ERK5 may provide a common bypass route, which rescues proliferation upon abrogation of ERK1 signaling. Thus, we accurately classified the tumor types from The Cancer Genome Atlas (TCGA) based on the expression levels of ERK1 and ERK5. We proposed a novel therapeutic strategy to overcome the above-mentioned compensatory mechanism in specific tumor types by co-targeting both ERK1 and ERK5. On the basis of the idea of overcoming ERK5 compensation mechanism, (ADTL-EI1712) as the first selective dual-target inhibitor of ERK1 and ERK5 was discovered to have potent antitumor effects and . Interestingly, this compound was found to induce regulated cell death accompanied by autophagy in MKN-74 cells. Taken together, our results warrant the potential of this dual-target inhibitor as a new candidate drug that conquers compensatory mechanism in certain tumor types.
ERK1 和 ERK5 被认为在几种类型的癌症中具有关键作用。在某些情况下，ERK5 可能提供了一种常见的旁路途径，在 ERK1 信号中断时挽救增殖。因此，我们根据 ERK1 和 ERK5 的表达水平，准确地对来自癌症基因组图谱 (TCGA) 的肿瘤类型进行了分类。我们提出了一种新的治疗策略，通过共同靶向 ERK1 和 ERK5，来克服特定肿瘤类型中的上述代偿机制。基于克服 ERK5 补偿机制的理念，我们发现了第一个选择性的 ERK1 和 ERK5 双重靶抑制剂（ADTL-EI1712），它具有很强的抗肿瘤作用和。有趣的是，该化合物被发现可诱导 MKN-74 细胞中的调控性细胞死亡伴随自噬。总之，我们的结果证明了这种双重靶抑制剂作为一种新的候选药物的潜力，它可以克服某些肿瘤类型中的代偿机制。
