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Purity: ≥98%
Vatalanib ((PTK787 or ZK 222584, cpg-79787) is a novel, potent and orally bioavailable inhibitor of VEGFR2/KDR with IC50 of 37 nM in a cell-free assay, it is less potent against VEGFR1/Flt-1, and is 18-fold against VEGFR3/Flt-4. It is an analog of anilinophthalazine that may have antitumor properties. Vatalanib binds to VEGFR 1 and 2's protein kinase domain, inhibiting it. Additionally, this substance binds to and inhibits c-Kit, c-Fms, and the PDGF receptor, among other related receptor tyrosine kinases.
| Targets |
VEGFR2/KDR (IC50 = 37 nM); VEGFR1/FLT1 (IC50 = 77 nM); VEGFR2/Flk1 (IC50 = 270 nM); PDGFRβ (IC50 = 580 nM); VEGFR3/FLT4 (IC50 = 660 nM)
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| ln Vitro |
Vatalanib also inhibits PDGFRβ, Flk, and c-Kit with IC50 values of 580 nM, 730 nM, and 270 nM, respectively. At an IC50 of 7.1 nM, vatalanib inhibits the thymidine incorporation that VEGF induces in HUVECs. It also suppresses VEGF-induced migration and survival of endothelial cells in the same dose range in a dose-dependent manner, without having an adverse effect on cells that do not express VEGF receptors[1]. According to a new study, vatalanib increases the levels of the protein Bax and decreases Bcl-xL and Bcl-2, which significantly inhibits the growth of hepatocellular carcinoma cells and enhances the IFN/5-FU-induced apoptosis[2].
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| ln Vivo |
Vatalanib results in dose-dependent suppression of the angiogenic response to VEGF and PDGF following a single oral dosage (25–100 mg/kg) in two models: one using growth factor implants, the other using tumor cell-driven angiogenesis. Vatalanib also inhibits the growth and metastases of multiple human carcinomas in nude mice within the same dose range, while having no discernible effect on bone marrow leukocytes or circulating blood cells[1].
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| Enzyme Assay |
Every GST-fused kinase is cultured in buffer conditions that are optimized. ATP in a 30 μL total volume for 10 minutes at room temperature, either with or without the test drug vatalanib. To stop the reaction, add 10 μL of 250 mM EDTA[1].
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| Cell Assay |
In 96-well plates coated with 1.5% gelatin, subconfluent HUVECs are seeded. A constant concentration of either VEGF (50 ng/mL), bFGF (0.5 ng/mL), or FCS (5%), with or without vatalanib, is added to the basal medium after 24 hours, replacing the growth medium. Additionally included as a control are wells devoid of growth factor. Cells are incubated for a further 24 hours after the addition of the BrdUrd labeling solution, and then they are fixed, blocked, and have peroxidase-labeled anti-BrdUrd antibody added. The 3,3',5,5'-tetramethylbenzidine substrate is then used to detect the bound antibody[1].
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| Animal Protocol |
On the dorsal flank of C57/C6 mice, a 0.5 mL porous Teflon chamber containing 0.8% w/v agar, 0.2% heparin (20 units/mL), growth factors (3 g/mL human VEGF, 2 g/mL human PDGF), or neither, is implanted s.c. Beginning one day prior to chamber implantation and continuing for five days thereafter, the mice are treated with either vehicle (water) or Vatalanib (12.5, 25 or 50 mg/kg dihydrochloride p.o. once daily). The treatment concludes with the mice's death and the removal of the chambers. Measurements of the tissue's hemoglobin content are used to determine the amount of blood present after the vascularized tissue surrounding the chamber is carefully removed and weighed[1].
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Rapid onset of absorption Metabolism / Metabolites Mainly through oxidative metabolism. Two pharmacologically inactive metabolites, CGP 84368/ZK 260120 and NVP AAW378/ZK 261557, having systemic exposure comparable to that of vatalanib, contributed mainly to the total systemic exposure. Biological Half-Life Approximately 6 hours. |
| References |
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| Additional Infomation |
Vatalanib is a member of the class of phthalazines that is phthalazine in which the hydrogens at positions 1 and 4have been replaced by a p-chlorophenylamino group and a pyridin-4-ylmethyl group, respectively. It is a multi-targeted tyrosine kinase inhibitor for all isoforms of VEGFR, PDGFR and c-Kit. It has a role as an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an angiogenesis inhibitor and a vascular endothelial growth factor receptor antagonist. It is a member of phthalazines, a member of pyridines, a member of monochlorobenzenes and a secondary amino compound.
Vatalanib (PTK787/ZK-222584) is a new oral antiangiogenic molecule that inhibits all known vascular endothelial growth factor receptors. Vatalanib is under investigation for the treatment of solid tumors. Vatalanib is an orally bioavailable anilinophthalazine with potential antineoplastic activity. Vatalanib binds to and inhibits the protein kinase domain of vascular endothelial growth factor receptors 1 and 2; both receptor tyrosine kinases are involved in angiogenesis. This agent also binds to and inhibits related receptor tyrosine kinases, including platelet-derived growth factor (PDGF) receptor, c-Kit, and c-Fms. See also: Vatalanib Succinate (annotation moved to). Drug Indication Used in combination with first- and second-line chemotherapy for the treatment of metastatic colorectal cancer and non-small cell lung cancer (NSCLC). Mechanism of Action Vatalanib potently inhibits vascular endothelial growth factor (VEGF) receptor tyrosine kinases, important enzymes in the formation of new blood vessels that contribute to tumor growth and metastasis. Pharmacodynamics Vatalanib is a novel oral angiogenesis inhibitor being developed by Schering (in collaboration with Novartis AG). Vatalanib selectively inhibits the tyrosine kinase domains of vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptor, and c-KIT. |
| Molecular Formula |
C20H15CLN4
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| Molecular Weight |
346.8129
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| Exact Mass |
346.098
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| Elemental Analysis |
C, 69.26; H, 4.36; Cl, 10.22; N, 16.15
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| CAS # |
212141-54-3
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| Related CAS # |
Vatalanib dihydrochloride;212141-51-0;Vatalanib succinate;212142-18-2
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| PubChem CID |
151194
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| Appearance |
White to off-white crystalline powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
587.8±50.0 °C at 760 mmHg
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| Melting Point |
209-212ºC
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| Flash Point |
309.3±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.711
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
407
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1[H])N([H])C1C2=C([H])C([H])=C([H])C([H])=C2C(C([H])([H])C2C([H])=C([H])N=C([H])C=2[H])=NN=1
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| InChi Key |
YCOYDOIWSSHVCK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H15ClN4/c21-15-5-7-16(8-6-15)23-20-18-4-2-1-3-17(18)19(24-25-20)13-14-9-11-22-12-10-14/h1-12H,13H2,(H,23,25)
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| Chemical Name |
N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine
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| Synonyms |
PTK787/ZK 222584; CGP-7978; PTK787; PTK 787; PTK-787; ZK 222584; ZK222584; ZK-222584; CGP79787D; CGP 79787; CGP-797870; ZK-232934
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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) |
DMSO: 21.3~100 mg/mL (50.6~360.4 mM)
Ethanol: ~6 mg/mL (~14.3 mM) Water: ~10 mg/mL (~23.8 mM) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8834 mL | 14.4171 mL | 28.8342 mL | |
| 5 mM | 0.5767 mL | 2.8834 mL | 5.7668 mL | |
| 10 mM | 0.2883 mL | 1.4417 mL | 2.8834 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 |
| NCT00072475 | Completed | Drug: vatalanib | Myelodysplastic Syndromes Leukemia |
Alliance for Clinical Trials in Oncology |
December 2003 | Phase 2 |
| NCT00268918 | Completed | Drug: PTK787 Drug: Docetaxel |
Ovarian Cancer Cervical Cancer |
Dana-Farber Cancer Institute | September 2005 | Phase 1 |
| NCT00117299 | Completed | Drug: PTK787/ZK222584 | Sarcoma | University of Helsinki | September 2004 | Phase 2 |
| NCT00056459 | Completed | Drug: Vatalanib | Colorectal Neoplasms Rectal Neoplasms |
Novartis | February 2003 | Phase 3 |
| NCT00056446 | Completed | Drug: Vatalanib | Colorectal Neoplasms Colonic Neoplasms |
Novartis Pharmaceuticals | January 2003 | Phase 3 |
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