Fruquintinib(HMPL-013)Potent and selective inhibitor of VEGFR 1, 2, 3 CAS# 1194506-26-7 |
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| Cas No. | 1194506-26-7 | SDF | Download SDF |
| PubChem ID | 44480399 | Appearance | Powder |
| Formula | C21H19N3O5 | M.Wt | 393.39 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | HMPL-013 | ||
| Solubility | DMSO : 5.88 mg/mL (14.95 mM; Need ultrasonic) | ||
| Chemical Name | 6-(6,7-dimethoxyquinazolin-4-yl)oxy-N,2-dimethyl-1-benzofuran-3-carboxamide | ||
| SMILES | CC1=C(C2=C(O1)C=C(C=C2)OC3=NC=NC4=CC(=C(C=C43)OC)OC)C(=O)NC | ||
| Standard InChIKey | BALLNEJQLSTPIO-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C21H19N3O5/c1-11-19(20(25)22-2)13-6-5-12(7-16(13)28-11)29-21-14-8-17(26-3)18(27-4)9-15(14)23-10-24-21/h5-10H,1-4H3,(H,22,25) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Fruquintinib (HMPL-013) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 33, 0.35, and 35 nM, respectively.In Vitro:Fruquintinib demonstrates potent inhibition on VEGF-A dependent KDR phosphorylation in HEK293-KDR cells and VEGF-A induced proliferation in primary HUVECs with IC50s of 0.6±0.2 nM and 1.7 nM, respectively. Similarly, potent VEGFR3 attenuation by fruquintinib is observed in primary HLECs, with IC50s of 1.5 nM and 4.2 nM for VEGF-C stimulated VEGFR3 phosphorylation and proliferation, respectively. Fruquintinib suppresses the tube branching, tube length and area in a concentration-dependent manner. The tubule length of primary HUVECs decreased by 74% and 94% at 0.03 and 0.3 μM of fruquintinib, respectively. Fruquintinib inhibits HUVEC tubule growth and CAM angiogenesis. Tube formation is suppressed significantly after treatment with fruquintinib at 0.3 μM for 18 hours[1].In Vivo:Gastric cancer BGC-823 model is found to be most sensitive to fruquintinib. In this model, fruquintinib inhibits tumor growth by 62.3% and 95.4∼98.6%, at 0.5 and 2 mg/kg once daily dosing, respectively. When the dose is elevated to 5 mg/kg and 20 mg/kg, the tumors regress by 24.1% and 48.6%, respectively. The level of anti-tumor growth activity of fruquintinib varies in different tumor xenograft models. Fruquintinib significantly decreases the micro-vessel density even at the lowest dose of 0.8 mg/kg[1]. References: | |||||
Fruquintinib(HMPL-013) Dilution Calculator
Fruquintinib(HMPL-013) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.542 mL | 12.71 mL | 25.4201 mL | 50.8401 mL | 63.5502 mL |
| 5 mM | 0.5084 mL | 2.542 mL | 5.084 mL | 10.168 mL | 12.71 mL |
| 10 mM | 0.2542 mL | 1.271 mL | 2.542 mL | 5.084 mL | 6.355 mL |
| 50 mM | 0.0508 mL | 0.2542 mL | 0.5084 mL | 1.0168 mL | 1.271 mL |
| 100 mM | 0.0254 mL | 0.1271 mL | 0.2542 mL | 0.5084 mL | 0.6355 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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IC50: 33 nmol/L, 35 nmol/L and 0.5 nmol/L for VEGFR1, 2, 3
VEGF/VEGFR signal has been proven to be an important target for development of novel cancer therapies. One challenging aspect in VEGFR inhibitors is to achieve sustained target inhibition at tolerable doses previously seen only with the long-acting biologics. Fruquintinib is a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy.
In vitro: Fruquintinib was found to inhibit VEGFR2 with an IC50 of 25 nmol/L. The kinase selectivity of fruquintinib was evaluated against a panel of 253 kinases. The results showed that fruquintinib inhibited VEGFR family members with weak inhibition of RET, FGFR-1 and c-kit kinases [1].
In vivo: Anti-tumor activity of fruquintinib was evaluated in a variety of tumor xenografts. The results from gastric cancer BGC-823 model seemed to indicate that the drug concentration needs to be at least maintained above EC85 for around 8 hours in order to achieve >80% tumor growth inhibition. BGC-823 was found to be most sensitive to fruquintinib [1].
Clinical trial: Fruquintinib (HMPL-013) is currently in Phase II clinical studies. Analysis of Phase I pharmacokinetic data revealed that at the maximum tolerated dose of once daily oral administration fruquintinib achieved complete VEGFR2 suppression for 24 hours/day [1].
Reference:
[1] Sun Q, Zhou J, Zhang Z, Guo M, Liang J, Zhou F, Long J, Zhang W, Yin F, Cai H, Yang H, Zhang W, Gu Y, Ni L, Sai Y, Cui Y, Zhang M, Hong M, Sun J, Yang Z, Qing W, Su W, Ren Y. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45.
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Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics.[Pubmed:24817647]
Cancer Chemother Pharmacol. 2014 Jul;74(1):95-115.
PURPOSE: This study evaluated the preclinical pharmacokinetics (PK) and disposition of fruquintinib (HMPL-013), a small molecule vascular endothelial growth factor receptors inhibitor. METHODS: In vitro and in vivo PK/ADME assays were conducted. Allometry and PK modeling/simulation were conducted to predict human PK parameters and the time course profiles. RESULTS: HMPL-013 has high permeability without efflux. It shows moderate oral bioavailability of 42-53 % and Tmax < 4 h in mouse, rat, dog and monkey, with exposure-dose linearity proved in rats and dogs. No significant food effect is on dog PK. HMPL-013 has moderately high tissue distribution. It majorly distributes in gastrointestinal tract, liver, kidney, adrenal and adipose. The plasma protein binding fraction is 88-95 % in mouse, rat, dog and human, invariable up to 10 microM. The in vivo clearance of HMPL-013 is low, consistent with the in vitro scaling. Three major oxidative metabolites were identified in liver microsomes of mouse, rat, dog, monkey and human. Dog is mostly similar to human regarding in vitro metabolism. Demethylation, hydroxylation and sequential glucuronidation are the major in vivo metabolic reactions. Direct urinary and biliary excretion of HMPL-013 is negligible. Metabolizing to M1 (demethylation), sequentially glucuronidating, followed by biliary excretion, and to a less extent, by urinary excretion, are important elimination pathways for HMPL-013 in rats. HMPL-013 has low risk of drug-drug interaction. It is predicted to have favorable human PK properties and low efficacious dose. CONCLUSION: HMPL-013 demonstrates good preclinical PK and enables successful human PK and dose projection. It is valuable for further clinical development.
