Discovery of a potent anticancer agent against pancreatic ductal adenocarcinoma targeting FAK with DFG-out state and JAK/Aurora kinases

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer because of the difficulty in diagnosis and its resistance to chemotherapy. Focal adhesion kinase (FAK) is found overexpressed in PDAC, and targeting FAK has been proved to impede the progress of PDAC. However, most of FAK inhibitors were reported to bind with FAK in a DFG-in conformation, leading to a limited anti-tumor effect in clinical studies. Herein, to develop FAK inhibitors targeting the inactive DFG-out conformation, a series of large aromatic rings were selected to improve the interaction with Phe565 of the DFG motif. Compound 26 was designed to effectively inhibit FAK and the proliferation of PANC-1 cells with IC 50 of 50.94 nM and 0.15 μM, respectively. Besides, compound 26 was proved to strongly suppress the proliferation, colony formation, migration, and invasion in FAK-overexpressing PDAC cells. This inhibitor was confirmed to induce the apoptosis and G2/M arrest in PANC-1 cells through the suppression of FAK/PI3K/Akt signal pathway. Meanwhile, compound 26 was found to simultaneously inhibit FAK with DFG-out conformation and JAK3/Aurora B (IC 50 of 9.99 nM and 0.49 nM, respectively). In vivo , compound 26 effectively inhibited the tumorigenesis and metastasis of PDAC with desirable biosafety. Overall, these results suggested that compound 26 was a promising candidate for the treatment of PDAC. • The conformation of FAK Phe565 is different in DFG-in/out state. • Compound 26 effectively suppresses the tumorigenesis and metastasis of PDAC. • Compound 26 simultaneously inhibits FAK and JAK3/Aurora B kinases.