School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China.
School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China; Guizhou Engineering Laboratory for Synthetic Drugs, Guiyang 550025, China.
Bioorg Chem. 2023 Nov;140:106792. doi: 10.1016/j.bioorg.2023.106792. Epub 2023 Aug 16.
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 IC values of 0.975 μM and 1.033 μM, which was much potent than the positive control TAE-226 (IC = 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 IC values of 0.2438 nM and 0.2691 nM, which was very close to TAE-226 (IC = 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.
受基于结构的药物设计策略的启发，我们设计并合成了一系列新型的 4-芳基氨基嘧啶衍生物，作为黏着斑激酶（FAK）抑制剂。大多数化合物对 U87-MG 细胞表现出优异的抗增殖活性。特别是化合物 8d 和 9b 的活性最高，IC 值分别为 0.975 μM 和 1.033 μM，比阳性对照 TAE-226（IC = 2.659 μM）的活性强得多。另一方面，这 27 个化合物对人正常 2BS 细胞的抑制作用较低。此外，化合物 8d 和 9b 对 FAK 的抑制活性也非常出色，IC 值分别为 0.2438 nM 和 0.2691 nM，与 TAE-226（IC = 0.1390 nM）非常接近。进一步的研究证明，化合物 8d 和 9b 可以诱导 U87-MG 细胞早期凋亡，并将细胞阻滞在 G2/M 期。作用机制表明，它们可以显著抑制 U87-MG 细胞集落形成、细胞迁移和 FAK 磷酸化。分子对接和分子动力学模拟研究表明，化合物 8d 和 9b 可以牢固地占据 FAK 的 ATP 结合位点。这些发现支持进一步研究化合物 8d 和 9b 作为 FAK 抑制剂用于抗肿瘤药物的发现。
