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Purity: ≥98%
Derazantinib (formerly known as ARQ 087) is a novel, orally bioavailable, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR (fibroblast growth factor receptor) addicted cell lines and tumors with IC50s of 4.5, 1.8, and 4.5 nM for FGFR1-3 respectively in biochemical assay, IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. The response to ARQ 087 treatment demonstrated that it inhibited the auto-phosphorylation of FGFR2 and other proteins downstream in the FGFR pathway (FRS2α, AKT, and ERK) in cells. Research on cell proliferation showed that ARQ 087 exhibited anti-proliferative activity in cell lines with FGFR dysregulation, encompassing mutations, fusions, and amplifications. Research on cell cycles in cell lines expressing high levels of FGFR2 protein revealed a positive correlation between the G1 cell cycle arrest induced by ARQ 087 and the subsequent induction of apoptosis. Furthermore, in FGFR2 modified SNU-16 and NCI-H716 xenograft tumor models with gene amplifications and fusions, ARQ 087 was successful in suppressing tumor growth in vivo. A subcohort of patients with intrahepatic cholangiocarcinoma who have been found to have FGFR2 gene fusions is part of the phase 1/2 clinical trial ongoing research on ARQ 087 (NCT01752920).
| Targets |
FGFR2 (IC50 = 1.8 nM); RET (IC50 = 3 nM); DDR2 (IC50 = 3.6 nM); PDGFRβ (IC50 = 4.1 nM); PDGFRβ (IC50 = 4.1 nM)
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| ln Vitro |
ARQ-087 has anti-proliferative action against cell lines with mutations, fusions, and amplifications caused by FGFR dysregulation. A positive correlation has been observed between the induction of apoptosis and ARQ 087-induced G1 cell cycle arrest in cell lines expressing high levels of FGFR2 protein. It is observed that ARQ 087 has a dose-dependent effect on FGFR1 and FGFR2 auto-phosphorylation. Using EC50 values of less than 0.123 μM, 0.185 μM, 0.463 μM, and greater than 10 μM, ARQ 087 suppresses the phosphorylation of full-length FGFR1, FGFR2, FGFR3, and FGFR4 in Cos-1 cells overexpressing them. ARQ 087 selectively inhibits both the fully active and inactive forms of FGFR kinase through an ATP competitive mechanism. Thus, by preventing FGFR from autophosphorylating and by inhibiting phosphorylated active kinase, ARQ 087 postpones FGFR activation[1].
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| ln Vivo |
ARQ 087 attenuates FGFR signaling in human xenograft tumors SNU-16, resulting in a decrease in phospho-FGFR, phospho-FRS2-α, and phospho-ERK, but has no effect on the total FGFR2 protein. In FGFR2 altered xenograft tumor models with gene amplifications and fusions (SNU-16 and NCI-H716), ARQ 087 effectively inhibits tumor growth in vivo. ARQ 087 was well tolerated at doses up to 75 mg/kg and showed effectiveness in several in vivo xenograft models[1].
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| Enzyme Assay |
The recombinant FGFR1 or FGFR2 proteins' kinase inhibitory activity was assessed by ARQ 087 using ATP and a biotinylated PYK2 peptide substrate. ARQ 087 was diluted ten times more in deionized water after being titrated in DMSO using a three-fold dilution scheme, resulting in a final DMSO concentration of 10%. In each well of a reaction plate, a volume (2.5 μL) of these dilutions or vehicle was added. In each well, a volume of 17.5 μL was used to add FGFR1 or FGFR2 to the 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) at a final concentration of 0.50 or 0.25 nM, respectively. ATP and substrate were added to assay buffer (5 μL) for a final reaction volume of 25 μL, with final concentrations of 0–1,000 μM ATP and 80 nM biotinylated-PYK2, following a 30-minute pre-incubation period. After 60 minutes of room temperature incubation, 10 μL of a stop/detection mixture prepared in assay buffer containing EDTA, AlphaScreenTM Streptavidin Donor, and P-TYR-100 Acceptor beads were added to the plates to stop them in the dark. The final concentrations of EDTA were 10 mM, and the amounts of both AlphaScreenTM Donor and Acceptor beads were 500 ng/well. The assay plates were read on a Perkin Elmer Envision Multilabel plate reader after being incubated for 60 minutes at room temperature in the dark. (wavelength of emission: 570 nm, wavelength of excitation: 640 nm). For tight-binding inhibitors, the effect of enzyme concentration was used. If the enzyme concentration was higher than the IC50 values under the used assay conditions, the IC50 values were, if needed, converted into Ki values.
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| Cell Assay |
After plating and incubating the cells for a full night at 37°C, they are subjected to a 24- or 72-hour treatment with 0.1 μM or 1 μM of ARQ 087. A FACS Calibur flow cytometer was used to analyze the cell cycle profiles after the cells were fixed, stained, and treated with the Cycletest Plus Reagent Kit.
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| Animal Protocol |
Mice: Female CB17 SCID mice (NCI-H716) or NCr nu/nu mice (SNU-16) with well-established (400 mg) subcutaneous tumors are given either vehicle control or a single oral dosage of derazantineb. Four hours after a single dose, samples of plasma and tumor are obtained. It is oral to administer derazantinib. For every group, the dosage volume is 10 mL/kg, or 0.1 mL/10 g of body weight.
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| References | |
| Additional Infomation |
Derazantinib is under investigation in clinical trial NCT03230318 (Derazantinib in Subjects With FGFR2 Gene Fusion Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma).
Derazantinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. Derazantinib binds to and potently inhibits the activity of FGFR subtypes 1, 2 and 3. This may result in the inhibition of FGFR-mediated signal transduction pathways, tumor cell proliferation, tumor angiogenesis and tumor cell death in FGFR-overexpressing tumor cells. FGFR, a receptor tyrosine kinase, is upregulated in many tumor cell types and plays a key role in tumor cellular proliferation, differentiation, angiogenesis and survival. |
| Molecular Formula |
C29H29FN4O
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| Molecular Weight |
468.58
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| Exact Mass |
468.232
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| Elemental Analysis |
C, 74.34; H, 6.24; F, 4.05; N, 11.96; O, 3.41
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| CAS # |
1234356-69-4
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| Related CAS # |
Derazantinib Racemate;2309668-44-6;Derazantinib dihydrochloride;1821329-75-2
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| PubChem CID |
46834118
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| Appearance |
White to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
615.1±65.0 °C at 760 mmHg
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| Flash Point |
325.8±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.632
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| LogP |
5.66
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
35
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| Complexity |
638
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COCCNCCC1=CC(NC2=NC=C3C[C@@H](C4=CC=CC=C4F)C5=CC=CC=C5C3=N2)=CC=C1
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| InChi Key |
KPJDVVCDVBFRMU-AREMUKBSSA-N
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| InChi Code |
InChI=1S/C29H29FN4O/c1-35-16-15-31-14-13-20-7-6-8-22(17-20)33-29-32-19-21-18-26(24-10-4-5-12-27(24)30)23-9-2-3-11-25(23)28(21)34-29/h2-12,17,19,26,31H,13-16,18H2,1H3,(H,32,33,34)/t26-/m1/s1
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| Chemical Name |
(6R)-6-(2-fluorophenyl)-N-[3-[2-(2-methoxyethylamino)ethyl]phenyl]-5,6-dihydrobenzo[h]quinazolin-2-amine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1341 mL | 10.6705 mL | 21.3411 mL | |
| 5 mM | 0.4268 mL | 2.1341 mL | 4.2682 mL | |
| 10 mM | 0.2134 mL | 1.0671 mL | 2.1341 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05174650 | Recruiting | Drug: Atezolizumab Drug: Derazantinib |
Intrahepatic Cholangiocarcinoma | Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest |
April 20, 2022 | Phase 2 |
| NCT04098692 | Completed | Drug: [14C]-Derazantinib capsule Drug: Derazantinib capsule |
Healthy Volunteers | Basilea Pharmaceutica | August 8, 2019 | Phase 1 |
| NCT03230318 | Completed | Drug: derazantinib | Combined Hepatocellular and Cholangiocarcinoma Intrahepatic Cholangiocarcinoma |
Basilea Pharmaceutica | November 10, 2017 | Phase 2 |
| NCT04045613 | Completed | Drug: Derazantinib 300 mg once daily monotherapy Drug: Derazantinib 200 mg twice daily monotherapy |
Urothelial Carcinoma | Basilea Pharmaceutica | August 2, 2019 | Phase 1 Phase 2 |
 Mode of FGFR inhibition for ARQ 087.PLoS One.2016 Sep 14;11(9):e0162594. |
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 Fig 2. ARQ 087 inhibits FGFR phosphorylation.
ARQ 087 arrests cells in the G1 cell cycle phase and induces apoptosis.PLoS One.2016 Sep 14;11(9):e0162594. |
 ARQ 087 inhibits the FGFR pathway in cancer cell lines.
ARQ 087 inhibits the FGFR pathway in xenograft tumors.PLoS One.2016 Sep 14;11(9):e0162594. |
 ARQ 087 activity in tumor growth models.PLoS One.2016 Sep 14;11(9):e0162594. |
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Animal weights in BaF3/FGFR2 animals dosed with ARQ 087.PLoS One.2016 Sep 14;11(9):e0162594. |
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