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.
- 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: [email protected].
- 5. Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: [email protected].
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.