Discovery of a Novel Dual-Target Inhibitor of ERK1 and ERK5 That Induces Regulated Cell Death to Overcome Compensatory Mechanism in Specific Tumor Types.,Journal of Medicinal Chemistry

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Discovery of a Novel Dual-Target Inhibitor of ERK1 and ERK5 That Induces Regulated Cell Death to Overcome Compensatory Mechanism in Specific Tumor Types.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-05 , DOI: 10.1021/acs.jmedchem.9b01896
Guan Wang ₁ , Yuqian Zhao ₁ , Yao Liu ₁ , Dejuan Sun ₁ , Yongqi Zhen ₂ , Jie Liu ₁ , Leilei Fu ₂ , Lan Zhang ₂ , Liang Ouyang ₁

Affiliation

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, 22ac (ADTL-EI1712) as the first selective dual-target inhibitor of ERK1 and ERK5 was discovered to have potent antitumor effects in vitro and in vivo. 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.

中文翻译：

发现一种新型的ERK1和ERK5双靶标抑制剂，该抑制剂可诱导调节的细胞死亡以克服特定肿瘤类型的补偿机制。

有人提出ERK1和ERK5在几种类型的癌症中起关键作用。在某些情况下，ERK5可能会提供一条通用的旁路路径，该路径可在ERK1信号被废除后挽救增殖。因此，我们根据ERK1和ERK5的表达水平准确地分类了《癌症基因组图谱》（TCGA）中的肿瘤类型。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补偿机制。基于克服ERK5补偿机制的思想，发现22ac（ADTL-EI1712）作为ERK1和ERK5的第一个选择性双重靶标抑制剂在体内和体外均具有有效的抗肿瘤作用。有趣的是，发现该化合物在MKN-74细胞中诱导受调节的细胞死亡并伴有自噬。在一起

更新日期：2020-02-20

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