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

Aberrant
activation of fibroblast growth factor receptors
(FGFRs)
has been identified as an oncogenic driver force for multiple cancer
types, making FGFRs a compelling target for anticancer therapy. Because
of the renewed interest in irreversible inhibitors, considerable efforts
have been made to find irreversible FGFR inhibitors. Herein, we discovered
a series of novel quinolone-based covalent pan-FGFR inhibitors by
further optimizing the lead compound (lenvatinib) under
the guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR1-4 with nanomolar activity and effectively suppressed the
proliferation of Huh-7 and Hep3B HCC cells. I-5 displayed
high selectivity against a panel of 369 kinases at 1 μM. The
irreversible binding to target proteins was characterized by liquid
chromatography 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 xenograft
mouse models.