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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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250mg |
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Purity: ≥98%
CH5183284 (also known as FF284; Debio-1347) is a novel, potent, selective and orally bioavailable FGFR inhibitor with potential antitumor activity. It inhibits the FGFR1/2/3/4 mutants with IC50 values of 9.3 nM, 7.6 nM, 22 nM, and 290 nM, in that order. Excellent in vivo antitumor efficaciousness is demonstrated in mice with tumors KG1, SNU-16, MFE280, UM-UC-14, RT112/84, or MKN-45.
Targets |
FGFR1 (IC50 = 9.3 nM); FGFR2 (IC50 = 7.6 nM); FGFR3 (IC50 = 22 nM); FGFR4 (IC50 = 290 nM)
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ln Vitro |
Zoligratinib is well-balanced in terms of stability in human liver microsomes and cellular antiproliferative activity against SNU-16. It is hypothesized that the distinction in how 8 interacts with M535 in FGFR1 and L889 in KDR accounts for the selectivity of 8's inhibition of FGFR over KDR[1]. For FGF-dependent proliferation, zoligratinib's IC50 is 29 nM, while for VEGF-dependent proliferation, it is 780 nM[2].
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ln Vivo |
Zoligratinib treatment shows a dose-dependent tumor regression (tumor growth inhibition (TGI)=106% at 30 mg/kg and 147% at 100 mg/kg) without apparent body weight loss. Significant in vivo efficacy of zoligratină treatment is also observed in xenograft mouse models with FGFR genetic alterations, including KG1 (leukemia, FGFR1OP-FGFR1 fusion), MFE280 (endometrial cancer, FGFR2 S252W mutation), UM-UC-14 (bladder cancer, FGFR3 S249C mutation), and RT112/84 (bladder cancer, FGFR3-TACC3 fusion)[1].
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Enzyme Assay |
A radiometric filter assay is used to measure the incorporation of 33Pi using a microplate scintillation counter in order to assess the inhibitory activity of CH5183284/Debio 1347 against FGFR1. Standard techniques are used in a homogeneous time-resolved fluorescence assay to measure the phosphorylation activities of LCK, EGFR, KIT, MET, SRC, BRK, FGFR2, Flt3, LTK, INSR, YES, ABL, EPHA2, ZAP70, Fyn, IGF1R, KDR, and PDGFR on substrate peptides. Using an EnVision HTS microplate reader, time-resolved fluorescence is quantified. IMAP FP Screening Express Progressive Binding System measures the activities of all the proteins on substrate peptides, including PKA, Akt1/PKBα, PKA, Cdk1/cyclin B, Cdk2/cyclin A, PKCα, PKCβ1, and PKCβ2. It uses an EnVision HTS microplate reader to measure fluorescence polarization.
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Cell Assay |
The 96-well plate wells containing 0.076−10,000 nM tested compounds (CH5183284) are filled with the cell lines, and the plate is then incubated at 37°C. The Cell Counting Kit-8 solution is added after 4 days of incubation, and absorbance at 450 nm is measured several hours later. The formula for calculating antiproliferative activity is 1-T/C) × 100 (%), where T and C stand for the absorbance at 450 nm of drug-treated cells (T) and untreated control cells (C)[1].
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Animal Protocol |
Rats: To evaluate the effects on blood pressure (BP), male Wistar rats weighing between 340 and 390 grams are implanted with a telemetry transmitter. Oral gavage of either the vehicle (0.5% carmellose sodium, 0.5% polysorbate 20, and 0.9% benzyl alcohol in purified water) or CH5183284/Debio 1347 (10 and 30 mg/kg) is performed once daily for four days in a row. Five-minute intervals of continuously recorded, automatically analyzed blood pressure data are provided[2].
Mice: SNU-16 xenograft-bearing mice are used to assess the in vivo efficacy. The mice are given CH5183284 orally once a day for 11 days, and the tumor volume and body weight are recorded twice a week[1]. |
References |
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Molecular Formula |
C20H16N6O
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Molecular Weight |
356.38
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Exact Mass |
356.14
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Elemental Analysis |
C, 67.40; H, 4.53; N, 23.58; O, 4.49
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CAS # |
1265229-25-1
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Related CAS # |
1265229-25-1;1265231-80-8;
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Appearance |
Solid powder
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SMILES |
CC1=NC2=C(N1)C=C(C=C2)N3C(=C(C=N3)C(=O)C4=CC5=CC=CC=C5N4)N
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InChi Key |
BEMNJULZEQTDJY-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C20H16N6O/c1-11-23-16-7-6-13(9-17(16)24-11)26-20(21)14(10-22-26)19(27)18-8-12-4-2-3-5-15(12)25-18/h2-10,25H,21H2,1H3,(H,23,24)
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Chemical Name |
[5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone
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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: ≥ 2.08 mg/mL (5.84 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 20.8 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: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.8060 mL | 14.0300 mL | 28.0599 mL | |
5 mM | 0.5612 mL | 2.8060 mL | 5.6120 mL | |
10 mM | 0.2806 mL | 1.4030 mL | 2.8060 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 |
NCT03344536 | Completed | Drug: Fulvestrant Drug: Debio 1347 |
Breast Cancer | Memorial Sloan Kettering Cancer Center |
November 10, 2017 | Phase 1 Phase 2 |
NCT01948297 | Terminated | Drug: Debio1347 (CH5183284) |
Solid Tumours | Debiopharm International SA | August 2013 | Phase 1 |
NCT03834220 | Terminated | Drug: Debio 1347 | Solid Tumor | Debiopharm International SA | March 22, 2019 | Phase 2 |
Selective inhibitory activity against FGFR1, FGFR2, and FGFR3. Mol Cancer Ther. 2014 Nov;13(11):2547-58. td> |
Selective antiproliferative activity of CH5183284/Debio 1347 against cancer cell lines harboring genetic alterations in FGFR. Mol Cancer Ther. 2014 Nov;13(11):2547-58. td> |
Selective antitumor activity of CH5183284/Debio 1347 in mouse models of cell lines harboring genetic alterations in FGFR. Mol Cancer Ther. 2014 Nov;13(11):2547-58. td> |