Design, Synthesis, and Biological Evaluation of 4-Arylamino Pyrimidine Derivatives as FAK Inhibitors and Tumor...

Focal adhesion kinase (FAK) is considered a promising target for the diagnosis and treatment of cancer. In this work, a series of N,N'-(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 (IC₅₀) ranging from 3.7 to 108.0 nM. Compound 13a, which exhibits high FAK enzyme inhibition with an IC₅₀ 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 [¹⁸F]17 (3.73 ± 0.10% ID/g) and [¹⁸F]13a (3.66 ± 0.02% ID/g). Compound [¹⁸F]18 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.