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| 25mg |
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Purity: ≥98%
GNF-5837 (GNF5837) is an orally bioavailable pan-TRK (TrkA, TrkB) inhibitor with potential antitumor activity. It inhibits TrkA/B with IC50s of 8 nM, and 12 nM, respectively. With an IC50 of 0.042 μM, GNF-5837 exhibits strong anti-proliferative activity against Ba/F3 cells in vitro. In a mouse xenograft model derived from RIE cells expressing both NGF and TRKA, GNF-5837 demonstrates high in vivo antitumor efficacy.
| Targets |
TrkB (IC50 = 9 nM); TrkC (IC50 = 7 nM); TrkA (IC50 = 11 nM)
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| ln Vitro |
GNF-5837 exhibits strong anti-Trk and strong anti-proliferation activity with an IC50 of 0.042 μM in Ba/F3 cells overexpressing the constitutively active Tel-TRKC fusion.[1]
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| ln Vivo |
GNF-5837 exhibits moderate bioavailability and low drug clearance in male Sprague-Dawley rats and Balb/c mice. GNF-5837 (100 mg/kg/d p.o.) dramatically suppresses tumor growth in mice containing Rie xenografts expressing TrkA and NGF.
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| Enzyme Assay |
TrkA and TrkC biochemical tests are performed using the HTRF technique. In the reaction buffer (50 mM HEPES pH 7.1, 10 mM MgCl2, 2 mM MnCl2, 0.01% BSA, 2.5 mM DTT, and 0.1 mM Na3VO4), the reaction mixture contains 1 μM peptide substrate, 1 μM ATP, and either 1.8 nM TrkA or 34 nM TrkC. The final volume of the mixture is 10 μL. Every reaction is conducted at room temperature in white ProxiPlateTM 384-well Plus plates, and after 60 minutes, 5 μL of 0.2mM EDTA is used to quench the reaction. The plates are incubated at room temperature for one hour after five μL of the detection reagents (0.05 μg SAXL and 2.5 ng PT66K) are added, and the EnVision reader is then used to read the results. Compounds are diluted into the assay mixture (final DMSO 0.5%), and 12-point (from 50 to 0.000282 μΜ) inhibition curves are used in duplicate to determine the IC50 values under assay conditions. The TrkB biochemical assay is performed using the microfluidic caliper method. In the reaction buffer that contained 100 mM HEPES, pH 7.5, 5 mM MgCl2, 0.01% Triton X-100, 0.1% BSA, 1 mM DTT, 10 μΜ Na3VO4, and 10 μΜBeta-Glycerophosphate, the reaction mixtures contained 1 μM peptide substrate, 10 μM ATP, and 2 nM TrkB. The Caliper EZ-reader is used to determine the products after the reactions are conducted for three hours at room temperature. The compounds are diluted into the assay mixture (final DMSO 1%), and 12-point (from 50 to 0.000282 μΜ) inhibition curves are used in duplicate to determine the IC50 values under the assay conditions.
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| Cell Assay |
Compounds are evaluated for their capacity to stop the growth of both wild-type and transformed Ba/F3 cells using constitutively expressed luciferase reporter and BCR-ABL, Tel-KDR, or other Tel fusion kinases. While the kinase-transformed Ba/F3 cells are kept in media devoid of IL-3, the parental Ba/F3 cells are kept in media containing recombinant mouse IL3. With the Liquid handling System Echo 555 (Labcyte), 7.5 nL of compounds are spotted into each well of 1536-well assay plates. 700 cells are subsequently plated in 7 μL culture media into each well of the assay plates, and compounds are tested at 3-fold serial dilutions ranging from 0.17 nM to 10 uM. The cells were then incubated at 37 °C for 48 hours. Each well receives 3 μL of Bright-Glo®, and ViewLux is used to read the plates.
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| Animal Protocol |
Mice bearing Rie xenografts expressing TrkA and NGF.
100 mg/kg/d p.o. |
| References |
| Molecular Formula |
C28H21F4N5O2
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|---|---|---|
| Molecular Weight |
535.49
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| Exact Mass |
535.163
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| Elemental Analysis |
C, 62.80; H, 3.95; F, 14.19; N, 13.08; O, 5.98
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| CAS # |
1033769-28-6
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| Related CAS # |
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| PubChem CID |
59397065
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| Appearance |
Orange to red solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
616.0±55.0 °C at 760 mmHg
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| Flash Point |
326.4±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.714
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| LogP |
6.33
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
39
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| Complexity |
930
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=C([H])C(C(F)(F)F)=C([H])C=1N([H])C(N([H])C1C([H])=C([H])C(C([H])([H])[H])=C(C=1[H])N([H])C1C([H])=C([H])C2/C(=C(\[H])/C3=C([H])C([H])=C([H])N3[H])/C(N([H])C=2C=1[H])=O)=O
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| InChi Key |
YYDUWLSETXNJJT-MTJSOVHGSA-N
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| InChi Code |
InChI=1S/C28H21F4N5O2/c1-15-4-6-19(35-27(39)37-25-11-16(28(30,31)32)5-9-22(25)29)13-23(15)34-18-7-8-20-21(12-17-3-2-10-33-17)26(38)36-24(20)14-18/h2-14,33-34H,1H3,(H,36,38)(H2,35,37,39)/b21-12-
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| Chemical Name |
1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-methyl-3-[[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-6-yl]amino]phenyl]urea
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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 (4.67 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 (4.67 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8674 mL | 9.3372 mL | 18.6745 mL | |
| 5 mM | 0.3735 mL | 1.8674 mL | 3.7349 mL | |
| 10 mM | 0.1867 mL | 0.9337 mL | 1.8674 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.
Efficacy of GNF-5837 (22) in Rie-TRKAmNGF xenograft model. ACS Med Chem Lett. 2012 Feb 9; 3(2): 140–145. |
X-ray crystal structure of compound 20 (stick representation; carbon in yellow, oxygen in red, nitrogen in blue, and fluorine in light blue) binding to the active site of TRKC kinase domain. ACS Med Chem Lett. 2012 Jan 1;3(2):140-5. |
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