Design, synthesis and biological evaluation of 4-arylamino-pyrimidine derivatives as focal adhesion kinase inhibitors

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.

Antitumor; FAK inhibitor; Pyrimidine; Thiophene.