Phosphamide-containing Diphenylpyrimidine Analogues (PA-DPPYs) As Potent Focal Adhesion Kinase (FAK) Inhibitors with Enhanced Activity Against Pancreatic Cancer Cell Lines

A family of phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) were synthesized as potent focal adhesion kinase (FAK) inhibitors. The PA-DPPY derivatives could significantly inhibit the FAK enzymatic activity at concentrations lower than 10.69 nM. Among them, compounds 7a and 7e were two of the most active FAK inhibitors, possessing IC values of 4.25 nM and 4.65 nM, respectively. In particular, compound 7e also displayed strong activity against AsPC cell line, with an IC of 1.66 μM, but show low activity against the normal HPDE6-C7 cells (IC > 20 μM), indicating its low cell cytotoxicity. Additionally, flow cytometry analysis showed that after treatment with 7e (8 μM, 72 h), both AsPC and Panc cells growth were almost totally inhibited, with a cell viability rate of 16.8% and 18.1%, respectively. Overall, compound 7e may be served as a valuable FAK inhibitor for the treatment of pancreatic cancer.