Kwong Ada J, Pham Thao N D, Oelschlager Hannah E, Munshi Hidayatullah G, Scheidt Karl A
Department of Chemistry, Department of Pharmacology, Feinberg School of Medicine, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States.
ACS Med Chem Lett. 2021 Sep 15;12(10):1559-1567. doi: 10.1021/acsmedchemlett.1c00376. eCollection 2021 Oct 14.
Growth, division, and development of healthy cells relies on efficient response to environmental survival cues. The conserved mitogen-activated protein kinase (MAPK) family of pathways interface extracellular stimuli to intracellular processes for this purpose. Within these pathways, the MEK family has been identified as a target of interest due to its clinical relevance. Particularly, MEK4 has drawn recent attention for its indications in pancreatic and prostate cancers. Here, we report two potent MEK4 inhibitors demonstrating significant reduction of phospho-JNK and antiproliferative properties against pancreatic cancer cell lines. Furthermore, molecular inhibition of MEK4 pathway activates the MEK1/2 pathway, with the combination of MEK1/2 and MEK4 inhibitors demonstrating synergistic effects against pancreatic cancer cells. Our inhibitors provided insight into the crosstalk between MAPK pathways and new tools for elucidating the roles of MEK4 in disease states, findings which will pave the way for better understanding of the MAPK pathways and development of additional probes.
健康细胞的生长、分裂和发育依赖于对环境生存信号的有效响应。保守的丝裂原活化蛋白激酶（MAPK）家族通路为此将细胞外刺激与细胞内过程相连接。在这些通路中，MEK家族因其临床相关性而被确定为一个感兴趣的靶点。特别是，MEK4因其在胰腺癌和前列腺癌中的作用而受到近期关注。在此，我们报告了两种有效的MEK4抑制剂，它们对胰腺癌细胞系显示出磷酸化JNK的显著降低和抗增殖特性。此外，MEK4通路的分子抑制激活了MEK1/2通路，MEK1/2和MEK4抑制剂的联合使用对胰腺癌细胞显示出协同作用。我们的抑制剂为深入了解MAPK通路之间的相互作用以及阐明MEK4在疾病状态中的作用提供了新工具，这些发现将为更好地理解MAPK通路和开发更多探针铺平道路。
