2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors of FAK with potent anti-gastric cancer activities

Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors of FAK with potent anti-gastric cancer activities

  • Bioorg Chem. 2023 Dec:141:106895. doi: 10.1016/j.bioorg.2023.106895.
Yang Liu 1,  Li-Jun Kong 2,  Na Li 1,  Yun-He Liu 1,  Mei-Qi Jia 3,  Qiu-Ge Liu 3,  Sai-Yang Zhang 4,  Jian Song 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 2 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Liaocheng Vocational and Technical College, Liaocheng 252000, China.
  • 3 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: saiyangz@zzu.edu.cn.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: mumuandzz@163.com.
PMID: 37797456 DOI: 10.1016/j.bioorg.2023.106895
Abstract

In this study, twenty-one novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors targeting FAK were designed and synthesized based on the structure of TAE-226, and the inhibitory effects of these compounds on both the FAK Enzyme and three Cancer cell lines (MGC-803, HCT-116, and KYSE30) were investigated. Among them, compound 12s displayed potent inhibitory potency on FAK (IC50 = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC50 values were 0.24, 0.45 and 0.44 μM, respectively) compared to TAE-226. Furthermore, compound 12s significantly inhibited FAK activation leading to the negative regulation of FAK-related signaling pathways such as Akt/mTOR and MAPK signaling pathways. Molecular docking study suggested that compound 12s could well occupy the ATP-binding pocket site of FAK similar to TAE-226. In addition, compound 12s also efficiently inhibited the proliferation, induced Apoptosis and cellular senescence in MGC-803 cells. In conclusion, compound 12s emerges a potent FAK Inhibitor that could exert potent inhibitory activity against gastric Cancer cells.

Keywords

2,4-Diaminopyrimidine; Anticancer activities; Cinnamyl; FAK.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156334
    FAK抑制剂
    FAK
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