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].
Derazantinib/德拉赞替尼(ARQ-087) 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Keloid fibroblasts (KFs)
2.5 μmol/L
48 hours
Derazantinib significantly suppressed the expression of PAI-1, FGFR1, collagen I, and α-SMA in KFs.
Biomedicines. 2023 Dec 5;11(12):3220.
Keloid fibroblasts (KFs)
2.5 μmol/L
48 hours
Derazantinib significantly inhibited the migration and invasion capability of KFs.
Biomedicines. 2023 Dec 5;11(12):3220.
Keloid fibroblasts (KFs)
0, 0.16, 0.31, 0.63, 1.25, 2.5, 5 μmol/L
48 hours
Derazantinib significantly inhibited the proliferation of KFs in a dose-dependent manner. Treatment with derazantinib at 5 μmol/L almost completely wiped off the KFs.
Biomedicines. 2023 Dec 5;11(12):3220.
Human keloid fibroblasts (KFs)
2.5 μmol/L
48 hours
Derazantinib significantly downregulated the expression of PAI-1, α-SMA, and collagen I, and inhibited the AKT and ERK signaling pathways.
Biomedicines. 2023 Dec 5;11(12):3220.
Human keloid fibroblasts (KFs)
2.5 μmol/L
48 hours
Derazantinib significantly inhibited the migration and invasion capabilities of KFs.
Biomedicines. 2023 Dec 5;11(12):3220.
Human keloid fibroblasts (KFs)
0, 0.16, 0.31, 0.63, 1.25, 2.5, 5 μmol/L
48 hours
Derazantinib significantly inhibited the proliferation of KFs in a dose-dependent manner, with 5 μmol/L concentration almost completely eliminating KFs. 2.5 μmol/L concentration showed significant inhibition on KFs but not on normal skin fibroblasts (Fbs).
Biomedicines. 2023 Dec 5;11(12):3220.
NCI-H716, SNU-16, KATO-III
0 to 3 μM
2 hours
To evaluate the inhibitory effect of ARQ 087 on the FGFR signaling pathway
PLoS One. 2016 Sep 14;11(9):e0162594.
COS-1 cells
0.123 μM, 0.185 μM, 0.463 μM, >10 μM
2 hours
To evaluate the inhibitory effect of ARQ 087 on the phosphorylation of FGFR1, FGFR2, FGFR3, and FGFR4
PLoS One. 2016 Sep 14;11(9):e0162594.
Derazantinib/德拉赞替尼(ARQ-087) 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude mice
AN3CA xenograft model
Oral
50-75 mg/kg
Once daily for 12 days
Evaluate the combined antitumor activity of ARQ 092 and ARQ 087, results showed significantly enhanced tumor growth inhibition
Anticancer Drugs. 2017 Jun;28(5):503-513.
BALB/C female athymic nude mice
Keloid xenografts
Local injection
1 mg/mL and 2 mg/mL
Once a week for four weeks
Derazantinib significantly reduced the weight of the transplanted keloids, inhibited collagen production, and disrupted angiogenesis.
Biomedicines. 2023 Dec 5;11(12):3220.
NCr nu/nu mice
SNU-16 and NCI-H716 xenograft models
Oral
50 mg/kg and 75 mg/kg
Once daily for 14 days
To evaluate the anti-tumor effect of ARQ 087 in FGFR2-driven tumor models
PLoS One. 2016 Sep 14;11(9):e0162594.
Zebrafish embryos
Tg(fli1a:EGFP)y1 transgenic zebrafish
Added to embryo water
0.1-3 μM
Treatment started at 6-8 hours post-fertilization
To investigate the effect of DZB on blood vessel morphogenesis, it was found that DZB interferes with multiple angiogenic processes linked to FGF and VEGF signaling, revealing its potential dual role as a potent anti-angiogenic treatment.
Pharmaceuticals (Basel). 2020 Dec 30;14(1):25
Sprague-Dawley (SD) rats
No specific model used
Oral
30 mg/kg
Single dose
To study the drug-drug interaction between derazantinib and naringin, results showed no significant effect of naringin pretreatment on the pharmacokinetic parameters of derazantinib
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