Home Protein Tyrosine Kinase FGFR inhibitor Derazantinib

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Derazantinib FGFR inhibitor

Cat.No.S8609

Derazantinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3, showing lower potency for FGFR4 (IC50=34 nM). It also inhibits RET, DDR2, PDGFRβ, VEGFR and KIT.
Derazantinib FGFR inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 468.57

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Quality Control

Chemical Information, Storage & Stability

Molecular Weight 468.57 Formula

C29H29FN4O

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1234356-69-4 -- Storage of Stock Solutions

Synonyms ARQ-087 Smiles COCCNCCC1=CC(=CC=C1)NC2=NC=C3CC(C4=CC=CC=C4C3=N2)C5=CC=CC=C5F

Solubility

In vitro
Batch:

DMSO : 93 mg/mL (198.47 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Mechanism of Action

Targets/IC50/Ki
FGFR2 [1]
(Cell-free assay)
1.8 nM
RET [1]
(Cell-free assay)
3 nM
DDR2 [1]
(Cell-free assay)
3.6 nM
PDGFRβ [1]
(Cell-free assay)
4.1 nM
PDGFRβ [1]
(Cell-free assay)
4.1 nM
FGFR1 [1]
(Cell-free assay)
4.5 nM
FGFR3 [1]
(Cell-free assay)
4.5 nM
KIT [1]
(Cell-free assay)
8.2 nM
KIT [1]
(Cell-free assay)
8.2 nM
PDGFRα [1]
(Cell-free assay)
9.5 nM
VEGFR1 [1]
(Cell-free assay)
11 nM
Src [1]
(Cell-free assay)
11 nM
Abl [1]
(Cell-free assay)
14 nM
VEGFR2 [1]
(Cell-free assay)
21 nM
VEGFR3 [1]
(Cell-free assay)
31 nM
FGFR4 [1]
(Cell-free assay)
34 nM
In vitro

ARQ-087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein show a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. ARQ 087 inhibits the auto-phosphorylation of FGFR1 and FGFR2 in a dose-dependent manner. In Cos-1 cells overexpressing full-length FGFR1, FGFR2, FGFR3 and FGFR4, ARQ 087 inhibits their phosphorylation with EC50 values of < 0.123 μM, 0.185 μM, 0.463 μM, >10 μM respectively. ARQ 087 inhibits FGFR kinase by an ATP competitive mechanism, and is capable of inhibiting both the inactive and fully active forms of the FGFR kinase. Hence, ARQ 087 delays FGFR activation by inhibiting its autophosphorylation, as well as inhibition of the phosphorylated active kinase[1].
Kinase Assay
Determination of Ki and mode of inhibition
Kinase inhibitory activity of ARQ 087 was determined for the recombinant FGFR1 or FGFR2 proteins utilizing a biotinylated PYK2 peptide substrate and ATP. ARQ 087 was titrated in DMSO utilizing a 3-fold dilution scheme, and then diluted 10-fold further in deionized water for a final DMSO concentration of 10%. A volume (2.5 μL) of these dilutions or vehicle was added to each well of a reaction plate. FGFR1 or FGFR2 was added to assay buffer (50 mM Tris, pH 8.0, 0.02 mg/mL BSA, 10 mM MgCl2, 1 mM EGTA, 10% glycerol, 0.1 mM Na3PO4, 1 mM DTT) to each well in a volume of 17.5 μL for a final concentration of 0.50 or 0.25 nM, respectively. After a 30-minute pre-incubation period, ATP and substrate were added in assay buffer (5 μL) for final concentrations of 0–1,000 μM ATP and 80 nM biotinylated-PYK2, for a final reaction volume of 25 μL. The plates were incubated for 60 minutes at room temperature, and then stopped in the dark by the addition of 10 μL stop/detection mixture prepared in assay buffer containing EDTA, AlphaScreen™ Streptavidin Donor and P-TYR-100 Acceptor beads for final concentrations of 10 mM EDTA and 500 ng/well of both AlphaScreen™ Donor and Acceptor beads. Assay plates were incubated for 60 minutes at room temperature in the dark, and the plates were read on a Perkin Elmer, Envision Multilabel plate reader. (excitation wavelength: 640 nm, emission wavelength: 570 nm). The effect of enzyme concentration was applied for tight-binding inhibitors, and if necessary, the IC50 values were converted into Ki values if the enzyme concentration was above the IC50 values under the assay conditions utilized.
In vivo

ARQ 087 attenuates FGFR signaling in SNU-16 human xenograft tumors, leading to a reduction in phospho-FGFR, phospho-FRS2-α, and phospho-ERK, while the total FGFR2 protein is unaffecte. ARQ 087 is effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions. ARQ 087 demonstrated efficacy in multiple in vivo xenograft models, and was well tolerated at doses up to 75 mg/kg[1].
References

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