Li Yanan, Cheng Ying, Zhang Maoqi, He Xiaoli, Kong Li, Zhou Kexiang, Zhou Yunfu, Li Lin, Tian Hongqi, Song Xiaomin, Cui Yukun
College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China.
Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, Tianjin 300192, China.
iScience. 2020 Jul 24;23(7):101254. doi: 10.1016/j.isci.2020.101254. Epub 2020 Jun 10.
Feedback circuits are one of the major causes underlying tumor resistance. Thus, compounds that target one oncogenic pathway with simultaneously blocking its compensatory pathway will be of great value for cancer treatment. Here, we develop a new MEK inhibitor designated as KZ-02 that exhibits unexpectedly higher cytotoxicity than its starting compound AZD6244, a well-known MEK inhibitor, in colorectal cancer (CRC). Subsequent kinase selectivity study identified Pim-1 as an additional cellular target for KZ-02. Further studies showed that AZD6244 and Pim-1 1 (a Pim-1 inhibitor) have a synergistic effect on CRC suppression. Mechanistic study revealed that MEK inhibition by AZD6244 leads to increased Pim-1 expression, which could be a general mechanism behind the compromised cell-killing activity of MEK inhibitors. KZ-02, despite increasing Pim-1 mRNA expression, simultaneously promotes Pim-1 proteasomal degradation. Therefore, we uncover a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1.
反馈回路是肿瘤耐药的主要原因之一。因此，能够靶向一条致癌途径并同时阻断其补偿途径的化合物对癌症治疗具有重要价值。在此，我们开发了一种名为KZ-02的新型MEK抑制剂，在结直肠癌（CRC）中，它表现出比其起始化合物AZD6244（一种著名的MEK抑制剂）更高的细胞毒性。随后的激酶选择性研究确定Pim-1是KZ-02的另一个细胞靶点。进一步研究表明，AZD6244和Pim-1抑制剂Pim-1 1对CRC抑制具有协同作用。机制研究表明，AZD6244抑制MEK会导致Pim-1表达增加，这可能是MEK抑制剂细胞杀伤活性受损背后的普遍机制。KZ-02尽管增加了Pim-1 mRNA表达，但同时促进了Pim-1的蛋白酶体降解。因此，我们发现了一种通过共同靶向MEK和Pim-1而具有显著增强抗肿瘤活性的新型MEK抑制剂KZ-02。
