Phosphamide-Containing Diphenylpyrimidine Analogues (PA-DPPYs) as Potent Focal Adhesion Kinase (FAK) Inhibitors with Enhanced Activity against Pancreatic Cancer Cell Lines

Publication date: Available online 30 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): He Liu, Bin Wu, Yang Ge, Jiaxin Xu, Shijie Song, Changyuan Wang, Jihong Yao, Kexin Liu, Yanxia Li, Xiuli Sun, Xiaodong Ma
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 within concentrations of lower than 10.69 nM. Among them, compounds 7a and 7e were two of the most active FAK inhibitors, possessing IC50 values of 4.25 nM and 4.65 nM, respectively. In particular, compound 7e also displayed strong activity against AsPC cell line, with an IC50 of 1.66 μM, but show low activity against the normal HPDE6-C7 cells (IC50 > 20 μM), indicating its low cell cytoxicity. Additionally, flow cytometry analysis showed that after treatment of 7e (8 μM, 72 h), both AsPC and Panc cells 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.

Graphical abstract

http://ift.tt/2yQrZJl