Details

Autor(en) / Beteiligte

• Liu, Yang
• Kong, Li-Jun
• Li, Na
• Liu, Yun-He
• Jia, Mei-Qi
• Liu, Qiu-Ge
• Zhang, Sai-Yang
• Song, Jian

Titel

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

Ist Teil von

• Bioorganic chemistry, 2023-12, Vol.141, p.106895-106895, Article 106895

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •A series of novel 2,4-diaminopyrimidine cinnamyl derivatives were designed and synthesized.•Compound 12s displayed inhibition of FAK with an IC50 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 (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.