Citation: Zhu Zhongzhen, Qiao Yu, Zhang Zihao, Gu Mingzhen, Wang Jin, Gao Zhiyu, Guo Wenhao, Liu Mingming, Li Rong. Design, Synthesis and Antitumor Evaluation of Novel Small Molecule Extracellular Regulated Protein Kinase (ERK) Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2020, 40(7): 1983-1990. doi: 10.6023/cjoc201912033 shu

Design, Synthesis and Antitumor Evaluation of Novel Small Molecule Extracellular Regulated Protein Kinase (ERK) Inhibitors

School of Pharmacy, Anhui Medical University, Hefei 230032

Corresponding author: Li Rong, aydlirong@163.com
Received Date: 23 December 2019
Revised Date: 26 April 2020

Fund Project: National Natural Science Foundation of China (No. 81972040)National Natural Science Foundation of China 81972040

Figures(4)

Extracellular regulated protein kinase (ERK) is a key kinase in the development of cancer. 12 urea compounds containing morpholin rings were designed and synthesized in search of novel ERK inhibitors by using merging strategy. The structures of all compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. ERK kinase activity and cell proliferation test results indicate that most of the target compounds have moderately inhibitory effects on human colorectal cancer cells SW480 and HCT-116, especially the IC₅₀ of 1-(4-fluorobenzyl)-3-(5-(4-morpholinophenyl)pyridin-2-yl)urea (18f) reaches 0.36 and 0.55 μmol/L, respectively, and has low toxicity to normal cells L02 (>10 μmol/L). At the same time, 18f can inhibit ERK kinase activity (IC₅₀=0.051 μmol/L) and phosphorylation level, but does not affect total ERK expression and upstream upstream activation of mitogen-activated extracellular signal-regulated kinase (MEK) activation. These research provides important reference for the further study of novel benzylpyridylurea ERK inhibitors.
- mitogen-activated protein kinases(MAPKs),
- extracellular regulated protein kinase (ERK),
- diarylurea,
- synthesis,
- antitumor activity
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