Discovery and Structural Optimization of Novel Quinolone Derivatives as Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors

Aberrantactivation of fibroblast growth factor receptors(FGFRs)has been identified as an oncogenic driver force for multiple cancertypes, making FGFRs a compelling target for anticancer therapy. Becauseof the renewed interest in irreversible inhibitors, considerable effortshave been made to find irreversible FGFR inhibitors. Herein, we discovereda series of novel quinolone-based covalent pan-FGFR inhibitors byfurther optimizing the lead compound (lenvatinib) underthe guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR1-4 with nanomolar activity and effectively suppressed theproliferation of Huh-7 and Hep3B HCC cells. I-5 displayedhigh selectivity against a panel of 369 kinases at 1 mu M. Theirreversible binding to target proteins was characterized by liquidchromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograftmouse models.