2. Academic Validation
  3. Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives as RAF-MEK-ERK pathway signaling pathway blockers: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships

Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives as RAF-MEK-ERK pathway signaling pathway blockers: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships

  • Eur J Med Chem. 2022 Oct 5:240:114579. doi: 10.1016/j.ejmech.2022.114579.
Qian Xie 1,  Yanni Shen 1,  Yanli Meng 1,  Jianhui Liang 1,  Jing Xu 1,  Shishao Liang 1,  Xiaoping Liu 2,  Yan Wang 3,  Chun Hu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016, China.
  • 2 Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016, China. Electronic address: lxp19730107@163.com.
  • 3 Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: yan.wang@siat.ac.cn.
  • 4 Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016, China. Electronic address: chunhu@syphu.edu.cn.
PMID: 35797896 DOI: 10.1016/j.ejmech.2022.114579
Abstract

The constitutive activation of ERK1/2 (RAF-MEK-ERK) signaling pathway has been widely observed in many types of tumors, and the blockade of ERK1/2 signaling pathway has been proved to reduce tumor growth. Therefore, ERK1/2 signaling pathway has become an interesting therapeutic target for Cancer therapy. Despite the successful development of BRaf and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Here we report the design, synthesis, biological activity of a series of novel pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives based on compound 1. Among them, the target compound N-(3-chlorophenyl)-2-((1,3-dimethyl-7-(4-methylpiperazin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)amino)acetamide (14m) exhibited excellent antiproliferative activity towards MCF-7, A375, SK-MEL-2 and SK-HEP-1 cells, with low cytotoxicity in C28/I2 cells. Tumor spheroid assay demonstrated the superior potency of 14m in inhibiting the growth of SK-HEP-1 spheroidal models. The mechanism of 14m to induce Cancer cell death was shown to suppress cell migrations, induce cell Apoptosis, decrease the levels of phosphorylated ERK and MEK in a dose-dependent manner and increase ROS production.

Keywords

Antitumor mechanism; Cytotoxic activity; Pyrido[2,3-d]pyrimidine; Structure-activity relationships; Synthesis.

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