Fibroblast growth factor receptor (FGFR) signaling plays an essential role in cellular proliferation, difference and migration. Derazantinib is a small-molecule kinase inhibitor for the FGFR family. It exhibits inhibitory activity against FGER2 with an IC50 of 1.8 nM and against FGFR1 and 3 with an IC50 of 4.5 nM. The Ki values of FGFR1 and FGFR2 were 2.7 nM and 0.68 nM, respectively. The autophosphorylation of the tyrosine residues of FGFR1 and FGFR2 were inhibited by derazantinib (0 - 5 μM) at a dose-dependent manner. Derazantinib also showed potent inhibitory functionality against other kinases, such as RET, DDR2, and FMS, with IC50 values of 3, 3.6 and 3.8, respectively. In COS-1 cells overexpressing FGFR1, FGFR2, FGFR3 and FGFR4, derazantinib inhibited the phosphorylation of FGFR1, FGFR2, FGFR3, and FGFR4 with EC50 values of <0.123 μM, 0.185 μM, 0.463 μM, and >10 μM respectively. Derazantinib inhibited multiple cell lines with FGFR1 or FGFR3 fusions with GI50 values between 0.13 - 1.4 μM. In SNU-16 tumor-bearing animals, oral administration of derazantinib (25, 50, 75 mg/kg) for 9 days reduced the phosphorylation of FGFR, FRS2-α, and ERK. Treatment of derazantinib at 50 mg/kg and 75 mg/kg for 15 days also demonstrated 69% and 83% tumor growth inhibition, respectively, in the Ba/F3-FGFR2 model[4].
作用机制
Derazantinib is a ATP-competitive inhibitor against FGFR. It contains a core structure, in which the aminopyrimidine moiety participates in a hinge interaction. Meanwhile, the hydrophobic region of the core stabilizes the downward G-loop conformation via non-polar interactions[4].
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