生物活性

• 描述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 K_i 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].

• 动物研究
  剂量	Mice: 25 mg/kg - 75 mg/kg[3] (p.o.)
  给药途径	p.o.