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A novel series of 4-arylamino-pyrimidine derivatives were designed and synthesized as focal adhesion kinase (FAK) inhibitors under the strategy of structure-based drug design. Most compounds performed excellent anti-proliferative activity against U87-MG cells. Especially, compounds 8d and 9b revealed the highest activity with IC50 values of 0.975 μM and 1.033 μM, which was much potent than the positive control TAE-226 (IC50 = 2.659 μM). On the other hand, the total 27 compounds exhibited low inhibition against human normal 2BS cells. Moreover, compounds 8d and 9b showed outstanding activity against FAK with IC50 values of 0.2438 nM and 0.2691 nM, which was very close to TAE-226 (IC50 = 0.1390 nM). Further studies proved that compounds 8d and 9b could induce U87-MG cell early apoptosis and arrest the cell at G2/M phase. The action mechanism indicated that they could significantly inhibit U87-MG cell clone formation, cell migration, and FAK phosphorylation. Molecular docking and molecular dynamics simulation investigations suggested that compounds 8d and 9b could firmly occupy the ATP binding site of FAK. These findings supported the further researches of compounds 8d and 9b as FAK inhibitors for antitumor drug discovery.
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
July 2022,
Molecular pharmaceutics,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
November 2023,
RSC medicinal chemistry,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
August 2018,
Bioorganic chemistry,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
April 2015,
Journal of enzyme inhibition and medicinal chemistry,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
March 2010,
European journal of medicinal chemistry,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
December 2021,
Bioorganic & medicinal chemistry letters,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
July 2023,
Bioorganic & medicinal chemistry letters,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
November 2020,
European journal of medicinal chemistry,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
February 2019,
MedChemComm,
Zhiwu Long, and
Yaqing Zuo, and
Rongrong Li, and
Yi Le, and
Yawen Dong, and
Longjia Yan
August 2017,
Bioorganic & medicinal chemistry,
