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Purity: ≥98%
Pazopanib HCl (formerly GW786034 HCl; GW-786034; trade name Votrient) is a novel and potent multi-targeted receptor tyrosine kinase inhibitor with potential anticancer activity. Its IC50 values in cell-free assays are 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM, and 146 nM, respectively, and it inhibits VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit, and c-Fms. Pazopanib specifically inhibits the receptors for platelet-derived growth factor (PDGF-R), c-kit, and vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3. This inhibition may lead to a reduction in angiogenesis in tumors where these receptors are raised. Advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas can be treated with the FDA-approved medicationpazopanib.
| Targets |
VEGFR1 (IC50 = 10 nM); VEGFR2 (IC50 = 30 nM); VEGFR3 (IC50 = 47 nM); PDGFRβ (IC50 = 84 nM); FGFR1 (IC50 = 140 nM); c-Kit (IC50 = 74 nM); c-Fms (IC50 = 146 nM)
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| ln Vitro |
Pazopanib exhibits good potency against all human VEGFR receptors, with IC50 values for VEGFR-1, -2, and -3 being 10, 30, and 47 nM, respectively. With IC50s of 84, 74, 140, and 146 nM, respectively, significant activity is also observed against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms. Pazopanib potently inhibits VEGF-induced phosphorylation of VEGFR-2 in HUVEC cells with an IC50 of approximately ~8 nM in cellular assays, in addition to inhibiting the proliferation of HUVECs induced by VEGF. Pazopanib possesses good pharmacokinetics in rat, dog, and monkey with low clearances (1.4-1.7 mL/min/kg) and good oral bioavailabilities (72, 47, 65%) dosed at 10, 1, and 5 mg/kg, respectively. Additionally, the cytochrome P450 profile is enhanced with inhibition greater than 10 μM against all isozymes examined, with the exception of 2C9 (7.9 μM)[1].
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| ln Vivo |
Mice given Pazopanib at a dose of 100 mg/kg twice a day for five days show a marked reduction in the amount of vascularization. After a typical three-week course of therapy, the antiangiogenic activity ofpazopanib is investigated in mice bearing established human xenografts (200−250 mm3) using HT29 (colon carcinoma), A375P (melanoma), and HN5 (head and neck carcinoma) tumors. The A375P model, which has a history of being more resistant to VEGFR-2 inhibitors, did not respond as well at any dose as the HN5 and HT29 xenografts did. Pazopanib does not show any antiproliferative activity against these human tumor lines (HT29, HN5, A375P) growing in serum-containing media at concentrations below 10 μM, suggesting that the observed inhibition of xenograft growth is operating through an antiangiogenic rather than an antitumor mechanism. Mice's body weight did not show any discernible changes during the course of the study, and the animals looked healthy and energetic[1]. In the group receiving Pazopanib eye drops, adherent leukocyte counts are higher than in the healthy animals and lower in the untreated diabetic animals. In healthy animals, the average number of leukocytes adhered to the retinal vasculature is 37.2±7.8, while in diabetic animals, it is 102±15.6, which is roughly three times greater than in healthy animals. The amount of leukocytes adhered in the retinal vasculature of animals treated with 0.5% w/v Pazopanib suspension is 69.5±9.5, which is significantly less than that of animals with diabetes[2].
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| Enzyme Assay |
The procedure for starting VEGFR enzyme assays involves adding 10 μL of activated VEGFR2 kinase solution (final concentration: 1 nM enzyme in 0.1 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.5, containing 0.1 mg/mL bovine serum albumin (BSA), 300 μM dithiothreitol (DTT)) to 10 μL of substrate solution (final concentration: 360 nM peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2), 75 μM ATP, 10 μM MgCl2], and 1 μL of titrated compound (Pazopanib) in DMSO. After 60 minutes of incubation at room temperature, 20 μL of 100 mM ethylene diamine tetraacetic acid (EDTA) is added to the plates to quench the reaction. Following the quenching process, 20 μL of HTRF reagents (final concentration: 15 nM Streptavidin-linked allophycocyanin, 1 nM antiphosphotyrosine antibody labeled in 0.1 mg/mL BSA, 0.1 M HEPES, pH 7.5) are added, and the plates are then incubated for a minimum of 10 minutes. Plate readers are used to measure the fluorescence at 665 nM[1].
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| Cell Assay |
5-bromo-2-deoxyuridine (BrdU) incorporation is a technique that uses commercially available kits to measure the impact of Pazopanib on cell proliferation. HUVEC is cultured in type 1 collagen coated 96-well plates with medium containing 5% fetal bovine serum (FBS) and incubated for the entire night at 37°C with 5% CO2. The cells' medium is removed, and each well is then filled with different dosages of Pazopanib in serum-free medium. The wells are then filled with either VEGF (10 ng/mL) or bFGF (0.3 ng/mL) after 30 minutes. After incubating the cells for an extra 72 hours, BrdU (10 μM) is added during the final 18 to 24 hours of the incubation process. ELISA is used to measure the amount of BrdU incorporated into cells at the end of incubation. A curve that fits the data is given by the formula y=Vmax(1−(x/(K+x))), where K is the IC50[1].
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| Animal Protocol |
Mice: In 8–12 week old nude mice, tumors are started by injecting tumor cell suspension. After tumors grow to a volume of 100–200 mm3, mice are randomly assigned to eight-groups. Pazopanib is given at 10, 30, or 100 mg/kg once or twice a day. When the study is over, the animals are put to death by breathing in CO2. Tumor volume (mm3) = (length×width2)/2 is the equation used to measure tumor volume twice a week using calipers. % inhibition=1−(average growth of the drug-treated population/average growth of the vehicle-treated control population) is a common way to report results.
Rats: Brown, male Norway Rats (BN; pigmented) weighing 200–250 g are acclimated for a minimum of two days before beginning any experiment. To induce diabetes, an intraperitoneal injection of 30 mg/mL of streptozotocin in 10 mM citrate buffer (pH 4.5) is given (60 mg/kg body weight) after an overnight fast of 12–16 hours. Following a 3- to 4-hour injection of streptozotocin, animals are fed a regular diet. A blood sample (5–10 μL) is drawn via a tail vein 24 hours later. A glucose monitor is used to measure the animals' blood glucose levels. Animals classified as diabetics have blood glucose levels higher than 250 mg/dL. There are three groups of animals. 12 people made up the groups "Healthy," "Diabetic," and "Diabetic+Treatment." Following diabetes induction, treatment is initiated right away. Animals in all groups are sacrificed on day 31, 16–17 hours after the last dose on day 30, after both eyes are dosed twice daily for 30 days with 0.5% w/v Pazopanib suspension (10 μL volume in each eye). |
| References |
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| Molecular Formula |
C21H23N7O2S.HCL
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|---|---|
| Molecular Weight |
473.98
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| Exact Mass |
473.1400719
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| Elemental Analysis |
C, 53.22; H, 5.10; Cl, 7.48; N, 20.69; O, 6.75; S, 6.76
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| CAS # |
635702-64-6
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| Related CAS # |
Pazopanib;444731-52-6;Pazopanib-13C,d3 hydrochloride;1261398-44-0
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| Appearance |
Solid powder
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| SMILES |
CC1=C(C=C(C=C1)NC2=NC=CC(=N2)N(C)C3=CC4=NN(C(=C4C=C3)C)C)S(=O)(=O)N.Cl
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| InChi Key |
MQHIQUBXFFAOMK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H23N7O2S.ClH/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16;/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25);1H
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| Chemical Name |
5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide;hydrochloride
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| Synonyms |
Pazopanib HCl; Pazopanib Hydrochloride; GW786034 Hydrochloride; GW786034 HCl; GW-78603; GW 786034; GW786034; GW-78603HCl; GW 786034 HCl; GW 786034; Pazopanib; trade name: Votrient.;
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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 |
| 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: ≥ 1 mg/mL (2.11 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (2.11 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 10.0 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. View More
Solubility in Formulation 3: ≥ 1 mg/mL (2.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/kg |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1098 mL | 10.5490 mL | 21.0979 mL | |
| 5 mM | 0.4220 mL | 2.1098 mL | 4.2196 mL | |
| 10 mM | 0.2110 mL | 1.0549 mL | 2.1098 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 |
| NCT01684397 | Recruiting | Biological: Bevacizumab Other: Pharmacological Study |
Stage IV Renal Cell Cancer Clear Cell Renal Cell Carcinoma |
Roswell Park Cancer Institute | November 21, 2012 | Phase 1 Phase 2 |
| NCT02180867 | Active Recruiting |
Drug: Doxorubicin Drug: Pazopanib |
Fibrosarcoma Liposarcoma |
National Cancer Institute (NCI) |
July 11, 2014 | Phase 2 Phase 3 |
| NCT01841736 | Active Recruiting |
Drug: Pazopanib Hydrochloride Other: Placebo Administration |
Atypical Carcinoid Tumor Metastatic Carcinoid Tumor |
National Cancer Institute (NCI) |
June 21, 2013 | Phase 2 |
| NCT01767636 | Active Recruiting |
Drug: Pazopanib Hydrochloride | Kidney Oncocytoma Stage IV Renal Cell Cancer |
Mayo Clinic | May 16, 2013 | Phase 2 |
| NCT01552356 | Active Recruiting |
Drug: Pazopanib Hydrochloride Other: Pharmacological Study |
Solid Neoplasm | National Cancer Institute (NCI) |
March 19, 2012 | Phase 1 |
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