本研究以结构基于药物设计策略，设计并合成了一系列新型的4-芳胺基嘧啶衍生物作为焦点黏附激酶（focal adhesion kinase，FAK）抑制剂。大多数化合物对U87-MG细胞具有出色的抗增殖活性。特别是化合物8d和9b表现出最高的活性，其IC50值分别为0.975 μM和1.033 μM，远远高于阳性对照TAE-226（IC50 = 2.659 μM）。另一方面，总共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表现出优异的活性，其IC50值分别为0.2438 nM和0.2691 nM，与TAE-226（IC50 = 0.1390 nM）非常接近。进一步研究证明，化合物8d和9b能够诱导U87-MG细胞的早期凋亡并阻滞细胞在G2/M期。行动机制研究表明，它们能够显著抑制U87-MG细胞的克隆形成、细胞迁移和FAK磷酸化。分子对接和分子动力学模拟的研究结果提示，化合物8d和9b能够牢固地占据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。 版权所有 © 2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.