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Telatinib mesylate (also known as Bay 57-9352 mesylate) is a potent and orally bioactive VEGFR2, VEGFR3, PDGFα, and c-Kit inhibitor with potential anticancer activity. Its IC50 values are 6 nM, 4 nM, 15 nM, and 1 nM for VEGFR2, VEGFR3, PDGFα, and c-Kit, respectively.
| Targets |
VEGFR2 (IC50 = 6 nM); VEGFR3 (IC50 = 4 nM); PDGFRα (IC50 = 15 nM); c-Kit (IC50 = 1 nM)
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|---|---|
| ln Vitro |
Telatinib inhibits the activity of the ATP-binding cassette G2 (ABCG2) efflux transporter, which increases the anticancer activity of ABCG2 substrate anticancer drugs. While Telatinib by itself has no discernible effect on drug-sensitive and drug-resistant cell lines, co-incubating ABCG2-overexpressing drug-resistant cell lines with Telatinib and ABCG2 substrate anticancer medications significantly lowers cellular viability. In cell lines that overexpress ABCG2, telibiba at 1 μM has no discernible effect on ABCG2 expression. In cell lines that overexpress ABCG2, telibib at 1 μM dramatically increases the intracellular accumulation of [3H]-mitoxantrone (MX)[2].
Telatinib significantly lowers the rate of [3H]-MX efflux from cells overexpressing ABCG2 at 1 μM. Moreover, in membrane vesicles overexpressing ABCG2, Telatinib strongly inhibits ABCG2-mediated transport of [3H]-E₂17βG[2].
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| ln Vivo |
Telatinib (15 mg/kg; oral dministration; every 2nd and 3rd day; total 12 times; male athymic NCR (nu/nu) nude mice) with Doxorubicin (1.8 mg/kg) significantly reduces the tumor size and growth rate of tumors overexpressing ABCG2[2].
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| Enzyme Assay |
In the membrane of High Five insect cells, the vanadate (Vi)-sensitive ATPase activity of ABCG2 is quantified. Membranes (2 μg/0.06 mL) are briefly incubated for 5 min at 37°C in ATPase assay buffer, either with or without 0.4 mM vanadate. Following this, they are incubated for an additional 5 min at 37°C with different concentrations of telatinib. Incorporating 4 mM Mg-ATP initiates the ATPase reaction. Reactions are halted by adding 0.05 mL of 10% SDS solution after 10 minutes of incubation at 37°C. A measurement is made of the released inorganic phosphate.
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| Cell Assay |
Telatinib exhibits low affinity towards the Tie-2 receptor, the Raf kinase pathway, the fibroblast growth factor receptor (FGFR) family, and the epidermal growth factor receptor family. Telatinib is metabolized by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) and a number of cytochrome P450 (CYP) isoforms, including CYP3A4/3A5, CYP2C8, CYP2C9, and CYP2C19. In humans, the primary biotransformation pathway for telatinib is the formation of its N-glucuronides. Telatinib is a weak substrate of the adenosine triphosphate binding cassette (ABC) B1 (ABCB1) transporter, according to in vitro research. Telatinib at 1 μM significantly enhances the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 μM significantly reduces the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibits ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. In cell lines that overexpress ABCG2, telibiba at 1 μM dramatically increases the intracellular accumulation of [3H]-mitoxantrone (MX). Furthermore, telatinib at 1 μM dramatically lowers the rate at which ABCG2-overexpressing cells efflux [3H]-MX. Additionally, in membrane vesicles overexpressing ABCG2, telatinib significantly inhibits ABCG2-mediated transport of [3H]-E217βG.
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| Animal Protocol |
Male athymic NCR (nu/nu) nude mice (13-15 g, age 4-5 weeks) injected with H460 and H460/MX20 cells[2]
15 mg/kg Oral dministration; every 2nd and 3rd day; total 12 times Nude mice ABCG2-overexpressing tumor xenograft model Briefly, H460 (1×106) and H460/MX20 (3×106) cells were injected s.c under the armpits. Tumors that fail to reach a volume of 30 mm3 at the start of treatment were not used in this study. The mice were randomized into four groups (n=8) and treated with one of the following regimens: (a) vehicle (10% N-methyl-pyrrolidinone, 90% polyethylene glycol 300) (q3d×6), (b) DOX (1.8 mg/kg, i.p., q3d×6), (c) telatinib dissolved in 10% N-methyl-pyrrolidinone, 90% polyethylene glycol 300 (15 mg/kg, p.o., every 2nd and 3rd day; total 12 times), and (d) DOX (1.8 mg/kg, i.p., q3d×6) + telatinib (15 mg/kg, p.o., every 2nd and 3rd day, given 1 h before giving DOX; total 12 times). DOX for injection was prepared by dissolving in saline. Tumor volume was measured using calipers and body weights were recorded. The two perpendicular diameters of tumors (termed A and B) were recorded every 3rd day and tumor volume (V) was estimated according to the formula published previously. At the end of the study, animals were euthanized by carbon dioxide, tumor tissue were excised and fixed in 10% formalin for immunohistochemistry. |
| References |
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| Additional Infomation |
Telatinib Mesylate is the orally bioavailable mesylate salt of the 17-allylaminogeldanamycin (17-AAG) small-molecule inhibitor of several receptor protein tyrosine kinases with potential antiangiogenic and antineoplastic activities. Telatinib binds to and inhibits the vascular endothelial growth factor receptors (VEGFRs) type 2 and 3, platelet-derived growth factor receptor beta (PDGFRb) and c-Kit, which may result in the inhibition of angiogenesis and cellular proliferation in tumors in which these receptors are upregulated. These telatinib-inhibited receptor protein tyrosine kinases are overexpressed or mutated in many tumor cell types and may play key roles in tumor angiogenesis and tumor cell proliferation. 17-AAG is a synthetic analogue of the benzoquinone ansamycin antibiotic geldanamycin and has also been found to inhibit the molecular chaperone Hsp90.
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| Molecular Formula |
C₂₁H₂₀CLN₅O₆S
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|---|---|
| Molecular Weight |
505.93
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| Exact Mass |
505.082
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| Elemental Analysis |
C, 49.85; H, 3.98; Cl, 7.01; N, 13.84; O, 18.97; S, 6.34
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| CAS # |
332013-26-0
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| Related CAS # |
Telatinib;332012-40-5
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| PubChem CID |
9870815
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
34
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| Complexity |
641
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CNC(=O)C1=NC=CC(=C1)COC2=NN=C(C3=C2OC=C3)NC4=CC=C(C=C4)Cl.CS(=O)(=O)O
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| InChi Key |
LCMLACPWPXITHP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H16ClN5O3.CH4O3S/c1-22-19(27)16-10-12(6-8-23-16)11-29-20-17-15(7-9-28-17)18(25-26-20)24-14-4-2-13(21)3-5-14;1-5(2,3)4/h2-10H,11H2,1H3,(H,22,27)(H,24,25);1H3,(H,2,3,4)
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| Chemical Name |
4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxymethyl]-N-methylpyridine-2-carboxamide;methanesulfonic acid
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| Synonyms |
BAY-57-9352; BAY 57-9352; 332013-26-0; Telatinib (mesylate); 332013-24-8; 571LVA9UMS; 2-Pyridinecarboxamide, 4-(((4-((4-chlorophenyl)amino)furo(2,3-d)pyridazin-7-yl)oxy)methyl)-N-methyl-, methanesulphonate (1:1); 2-Pyridinecarboxamide,4-[[[4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl]oxy]methyl]-N-methyl-, mono(4-methylbenzenesulfonate); 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxymethyl]-N-methylpyridine-2-carboxamide;methanesulfonic acid; BAY 57-9352; BAY57-9352
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: ~250 mg/mL (~494.1 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 | 1.9766 mL | 9.8828 mL | 19.7656 mL | |
| 5 mM | 0.3953 mL | 1.9766 mL | 3.9531 mL | |
| 10 mM | 0.1977 mL | 0.9883 mL | 1.9766 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 |
| NCT03175497 | Completed | Drug: Telatinib Mesylate | Solid Tumor, Adult | Taizhou EOC Pharma Co., Ltd. | July 25, 2017 | Phase 1 |
Br J Cancer. 2008 Nov 4; 99(10): 1579–1585. |
Geometric mean telatinib plasma concentration vs time profiles on day 14 of cycle 1. Br J Cancer. 2008 Nov 4; 99(10): 1579–1585. |
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