Use of Apatinib as a Bait to Fish its Unexpected Kinase Targets from the Hepatocellular Carcinoma Druggable Kinome

Apatinib is a tyrosine kinase inhibitor that cognately blocks the kinase activity of vascular endothelial growth factor receptor (VEGFR) signaling for the treatment of advanced gastric cancer (GC). However, the drug is also clinically found to reposition a significant suppressing potency on hepatocellular carcinoma (HCC). In this study, we reported the successful use of Apatinib as a bait to fish its potential kinase targets from the HCC druggable kinome pool. In the procedure, cell viability assays observed that the Apatinib has a potent cytotoxicity on human HCC cell lines. Dynamics simulations and affinity scoring systematically created an intermolecular interaction profile of Apatinib with ontologically enriched kinases in the HCC druggable kinome, from which the top-hit kinases were considered as potential candidates. It is revealed that the inhibitor has a weak potency on the well-established HCC target of ErbB pathway, but exhibits potent activity against some known targets or regulators of HCC. In particular, kinase assays substantiated that Apatinib can effectively inhibit four FGFR family members with moderate or high activity. In addition, the clinical FGFR1 gatekeeper mutation V561M was also observed to considerably impair the inhibitory activity, thus causing a drug resistance. Molecular modeling suggested that the Apatinib adopts two distinct binding modes to separately interact with wild-type and gatekeeper-mutant FGFR1 kinase domain.