Hwang Jeonghye, Moon Hyejin, Kim Hakwon, Kim Ki-Young
Department of Genetics and Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea.
Department of Applied Chemistry, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Republic of Korea.
Curr Issues Mol Biol. 2023 Jul 24;45(7):6154-6169. doi: 10.3390/cimb45070388.
Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase (MAPK) family, is involved in key cellular processes. However, overexpression and upregulation of ERK5 have been reported in various cancers, and ERK5 is associated with almost every biological characteristic of cancer cells. Accordingly, ERK5 has become a novel target for the development of anticancer drugs as inhibition of ERK5 shows suppressive effects of the deleterious properties of cancer cells. Herein, we report the synthesis and identification of a novel ERK5 inhibitor, MHJ-627, and verify its potent anticancer efficacy in a yeast model and the cervical cancer HeLa cell line. MHJ-627 successfully inhibited the kinase activity of ERK5 (IC: 0.91 μM) and promoted the mRNA expression of tumor suppressors and anti-metastatic genes. Moreover, we observed significant cancer cell death, accompanied by a reduction in mRNA levels of the cell proliferation marker, proliferating cell nuclear antigen (), following ERK5 inhibition due to MHJ-627 treatment. We expect this finding to serve as a lead compound for further identification of inhibitors for ERK5-directed novel approaches for oncotherapy with increased specificity.
细胞外信号调节激酶5（ERK5）是丝裂原活化蛋白激酶（MAPK）家族的成员，参与关键的细胞过程。然而，已有报道称ERK5在多种癌症中过表达和上调，并且ERK5与癌细胞的几乎每一种生物学特性都相关。因此，由于抑制ERK5显示出对癌细胞有害特性的抑制作用，ERK5已成为开发抗癌药物的新靶点。在此，我们报告了一种新型ERK5抑制剂MHJ-627的合成与鉴定，并在酵母模型和宫颈癌HeLa细胞系中验证了其强大的抗癌功效。MHJ-627成功抑制了ERK5的激酶活性（IC：0.91μM），并促进了肿瘤抑制因子和抗转移基因的mRNA表达。此外，在MHJ-627处理导致ERK5抑制后，我们观察到癌细胞显著死亡，同时细胞增殖标志物增殖细胞核抗原（）的mRNA水平降低。我们期望这一发现能够作为一种先导化合物，用于进一步鉴定针对ERK5的抑制剂，从而开发出特异性更高的新型肿瘤治疗方法。
