College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, China.
College of Chemistry and Chemical Engineering, Anyang Normal University, No. 436 Xian'ge Road, Anyang 455000, Henan Province, China.
Mol Pharm. 2022 Jul 4;19(7):2471-2482. doi: 10.1021/acs.molpharmaceut.2c00180. Epub 2022 Apr 28.
Focal adhesion kinase (FAK) is considered a promising target for the diagnosis and treatment of cancer. In this work, a series of ,'-(4-((5-bromo-2-(phenylamino)pyrimidin-4-yl)amino)-1,3-phenylene)diacetamide derivatives were synthesized and evaluated as FAK inhibitors and radiotracers. The studied compounds, possessing the same phenylene-diacetamide chain, exhibited high to moderate enzyme inhibition values (IC) ranging from 3.7 to 108.0 nM. Compound , which exhibits high FAK enzyme inhibition with an IC value of 3.7, could effectively suppress the tumor growth. Furthermore, three compounds were radiolabeled with F-18. Among them, a higher tumor uptake value was observed for [F] (3.73 ± 0.10% ID/g) and [F] (3.66 ± 0.02% ID/g). Compound [F] displayed the highest tumor/blood (35.75) value at 120 min postinjection. In addition, the results from docking studies revealed the binding mechanism of the studied compounds. The findings of this study may provide useful guidance to improve the development of radiotracers and enzyme inhibitors.
黏着斑激酶（FAK）被认为是癌症诊断和治疗的有前途的靶点。在这项工作中，合成了一系列，'-(4-((5-溴-2-(苯氨基)嘧啶-4-基)氨基)-1,3-亚苯基)二乙酰胺衍生物，并将其作为 FAK 抑制剂和放射性示踪剂进行了评估。所研究的化合物具有相同的亚苯基-二乙酰胺链，表现出高至中等的酶抑制值（IC），范围为 3.7 至 108.0 nM。化合物，表现出 3.7 的高 FAK 酶抑制作用，能够有效抑制肿瘤生长。此外，用 F-18 标记了三种化合物。其中，[F]（3.73 ± 0.10% ID/g）和[F]（3.66 ± 0.02% ID/g）观察到更高的肿瘤摄取值。化合物 [F]在注射后 120 分钟显示出最高的肿瘤/血液（35.75）比值。此外，对接研究的结果揭示了所研究化合物的结合机制。本研究的结果可能为改进放射性示踪剂和酶抑制剂的开发提供有用的指导。
