Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors
Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors
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DOI：
10.1021/acs.jmedchem.2c01244
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发表时间：
2022-10-07
影响因子：
7.3
通讯作者：
Liu, Bo
中科院分区：
文献类型：
--
作者：
Fu, Leilei;Chen, Siwei;Liu, Bo
细胞外信号调节蛋白激酶1/2(ERK1/2)是唯一已知的MEK1/2底物，位于Ras-RAF-MEK-ERK(MAPK)通路的下游，与肿瘤的异常激活和不良预后有关。到目前为止，RAS、RAF和MEK的几种小分子抑制剂被报道在癌症治疗中取得了快速进展，但仍存在获得性耐药，从而削弱了这些抑制剂的治疗效果。最近，选择性抑制ERK1/2被认为是一种潜在的肿瘤治疗策略，不仅可以有效地阻断MAPK通路，而且可以克服Ras、RAF和MEK上游突变所导致的耐药性。在此，我们综述了ERK1/2在临床前和临床试验中的致癌作用、关键的信号网络以及ERK1/2的单靶点和双靶点抑制物。总之，这些鼓舞人心的发现为发现更多的ERK1/2小分子抑制剂作为改进癌症治疗的候选药物提供了新的曙光。
Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream of the RAS-RAF-MEK-ERK (MAPK) pathway and is associated with the abnormal activation and poor prognosis of cancer. To date, several small-molecule inhibitors of RAS, RAF, and MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening the therapeutic efficacy of these inhibitors. Recently, selective inhibition of ERK1/2 has been regarded as a potential cancer therapeutic strategy that can not only effectively block the MAPK pathway but also overcome drug resistance caused by upstream mutations in RAS, RAF, and MEK. Herein, we summarize the oncogenic roles, key signaling network, and the single-and dual-target inhibitors of ERK1/2 in preclinical and clinical trials. Together, these inspiring findings shed new light on the discovery of more small-molecule inhibitors of ERK1/2 as candidate drugs to improve cancer therapeutics.