1. Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors of FAK with potent anti-gastric cancer activities.
- Author
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Liu, Yang, Kong, Li-Jun, Li, Na, Liu, Yun-He, Jia, Mei-Qi, Liu, Qiu-Ge, Zhang, Sai-Yang, and Song, Jian
- Subjects
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BIOSYNTHESIS , *CELLULAR aging , *CANCER cells , *MOLECULAR docking , *CELLULAR signal transduction - Abstract
[Display omitted] • A series of novel 2,4-diaminopyrimidine cinnamyl derivatives were designed and synthesized. • Compound 12s displayed inhibition of FAK with an IC 50 value of 47 nM. • Compound 12s exhibited potent antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells. • Compound 12s effectively inhibited the proliferation, induced apoptosis and induced cellular senescence in MGC-803 cells. 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 (IC 50 = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC 50 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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