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Purity: ≥98%
Telatinib (formerly BAY57-9352) is an orally bioavailable multi-kinase (e.g. VEGFR, PDGFR) inhibitor with potential antineoplastic activity. In vitro and in vivo chemotherapeutic multidrug resistance mediated by the ABCG2 efflux transporter was addressed by the development of telanib by the Bayer company.
| Targets |
VEGFR2 (IC50 = 6 nM); VEGFR3 (IC50 = 4 nM); c-Kit (IC50 = 1 nM); PDGFRα (IC50 = 15 nM)
Telatinib (BAY 57-9352) inhibits VEGFR1 (IC₅₀ = 4 nM), VEGFR2 (IC₅₀ = 6 nM), VEGFR3 (IC₅₀ = 11 nM), PDGFRα (IC₅₀ = 21 nM), and PDGFRβ (IC₅₀ = 18 nM) [1] Telatinib (BAY 57-9352) shows weak inhibitory activity against c-Kit (IC₅₀ = 160 nM) and no significant effect on EGFR (IC₅₀ > 1000 nM) [2] |
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| ln Vitro |
Telatinib has IC50 values that are 0.66, 0.17, and 2.5 times higher for VEGFR3, c-Kit, and PDGFRβ than VEGFR2, respectively, compared to 18, 20, and 16 times higher for Vatalanib.These differences suggest that Telatinib may be more beneficial than Vatalanib. Telatinib suppresses VEGF-dependent proliferation of human umbilical vein endothelial cells with an IC50 of 26 nM, inhibits VEGFR2 autophosphorylation in a whole-cell assay with an IC50 of 19 nM, and blocks PDGF-stimulated growth of human aortic smooth muscle cells with an IC50 of 249 nM.[3] Telatinib has minimal inhibitory effect on the Tie-2 receptor, fibroblast growth factor receptor (FGFR) family, Raf kinase pathway, and epidermal growth factor receptor family.[4]
Telatinib (BAY 57-9352) dose-dependently inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) with an IC₅₀ of 12 nM. At 50 nM, it suppressed HUVEC migration by ~80% and tube formation by ~85%, and blocked VEGF-mediated phosphorylation of VEGFR2 and downstream Akt/ERK1/2 signaling [1] Telatinib (BAY 57-9352) inhibited the proliferation of colorectal cancer cell lines (HCT-116, IC₅₀ = 3.8 μM; SW480, IC₅₀ = 4.5 μM) by suppressing autocrine VEGF/PDGF signaling. It induced G1 phase cell cycle arrest in HCT-116 cells at 5 μM [2] Telatinib (BAY 57-9352) enhanced the antitumor activity of oxaliplatin in vitro. Combination of 20 nM telatinib with 1 μM oxaliplatin increased apoptosis of HCT-116 cells by ~35% compared to oxaliplatin alone [4] |
| ln Vivo |
Telatinib treatment significantly inhibits tumor growth and metastasis by blocking VEGFR signaling and subsequently tumor angiogenesis, as tumor development and metastasis are attributed to a deregulated VEGFR signal pathway. Telatinib therapy significantly reduces both endothelium-dependent and endothelium-independent vasodilation, as well as capillary density, which increases both systolic and diastolic blood pressure. It also significantly inhibits tumor angiogenesis.[1] When administered alone, telatinib has a strong anti-tumor effect in a number of human tumor xenograft models, including dose-dependently MDA-MB-231 breast cancer, Colo-205 colon cancer, DLD-1 colon cancer, and H460 non-small cell lung cancer in addition to pancreatic and prostate carcinoma.[2]
Telatinib (BAY 57-9352) inhibited tumor growth in nude mice bearing HCT-116 colorectal cancer xenografts when administered orally at 60 mg/kg/day for 28 days. Tumor volume was reduced by ~65% compared to the control group, and intratumoral microvessel density (CD31-positive) decreased by ~70% [2] Telatinib (BAY 57-9352) suppressed liver metastasis of colorectal cancer cells (SW620) in nude mice. Oral administration of 40 mg/kg/day for 35 days reduced the number of liver metastatic nodules by ~60% [1] In a phase II clinical study of patients with advanced gastric cancer, Telatinib (BAY 57-9352) (900 mg orally twice daily) showed a disease control rate (stable disease + partial response) of 42%, with a median progression-free survival of 3.5 months [3] In patients with advanced non-small cell lung cancer (NSCLC), Telatinib (BAY 57-9352) (900 mg twice daily) resulted in a partial response rate of 8% and stable disease in 36% of patients, with a median overall survival of 6.8 months [4] |
| Enzyme Assay |
The ATPase activity of ABCG2 in the membrane of High Five insect cells is measured in relation to vanadate (Vi). In summary, membrane (2 μg/0.06 mL) are incubated for 5 minutes at 37°C in ATPase assay buffer, either with or without 0.4 mM vanadate. Subsequently, they are incubated for 5 minutes at 37°C with different concentrations of telatinib. 4 mM Mg-ATP is added to initiate the ATPase reaction. Ten minutes of incubation at 37°C are needed to stop the reactions, and then 0.05 mL of 10% SDS solution is added. It measures the amount of freed inorganic phosphate.
Recombinant VEGFR1, VEGFR2, VEGFR3, PDGFRα, and PDGFRβ kinase domains were individually incubated with ATP and specific peptide substrates in the presence of serial dilutions of Telatinib (BAY 57-9352). Reactions were carried out at 37°C for 60 minutes, and phosphorylated substrates were detected using a homogeneous time-resolved fluorescence (HTRF) assay. Inhibition rates were calculated by comparing fluorescence intensity with vehicle controls, and IC₅₀ values were derived from dose-response curves [1] Recombinant c-Kit and EGFR kinase domains were tested using the same protocol to assess selectivity. The reaction conditions were identical, and IC₅₀ values were determined to confirm weak or no inhibition of these kinases [2] |
| 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. In cell lines that overexpress ABCG2, telatinib at 1 μM dramatically increases the intracellular accumulation of [3H]-mitoxantrone (MX). Moreover, the rate of [3H]-MX efflux from ABCG2-overexpressing cells is markedly decreased by telatinib at 1 μM. Moreover, in membrane vesicles overexpressing ABCG2, telatinib dramatically reduces ABCG2-mediated transport of [3H]-E217βG.
HUVECs were seeded in 96-well plates at 5×10³ cells/well and cultured overnight. Telatinib (BAY 57-9352) (1-100 nM) was added 1 hour before stimulation with VEGF (50 ng/mL). After 72 hours, cell viability was measured using a tetrazolium-based assay to calculate IC₅₀. For Western blot analysis, HUVECs were treated with 10-50 nM drug and VEGF, then lysed and probed with antibodies against phosphorylated VEGFR2, Akt, ERK1/2, and GAPDH [1] HCT-116 and SW480 cells were seeded in 96-well plates and treated with Telatinib (BAY 57-9352) (0.5-10 μM) for 72 hours. Cell viability was assessed by MTT assay. HCT-116 cells were treated with 5 μM drug for 24 hours, fixed, stained with propidium iodide, and analyzed by flow cytometry for cell cycle distribution [2] HCT-116 cells were treated with Telatinib (BAY 57-9352) (10-40 nM) alone or in combination with oxaliplatin (1 μM) for 48 hours. Apoptosis was detected by Annexin V-FITC/PI staining, and the expression of apoptotic markers (cleaved caspase-3) was analyzed by Western blot [4] |
| Animal Protocol |
Mice: Four treatment regimens are administered to the mice, which are randomized into the following groups: (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 third 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). To prepare DOX for injection, dissolve it in saline. Body weights are noted and calipers are used to measure the tumor volume.
Nude mice bearing HCT-116 colorectal cancer xenografts (100-150 mm³) were randomly divided into control and treatment groups. Telatinib (BAY 57-9352) was suspended in 0.5% carboxymethylcellulose and administered orally at 60 mg/kg/day for 28 days. Tumor volume was measured every 3 days, and mice were euthanized to collect tumors for CD31 immunostaining [2] Nude mice were intrahepatically injected with SW620 colorectal cancer cells to establish a liver metastasis model. Two days later, mice were treated with Telatinib (BAY 57-9352) orally at 40 mg/kg/day for 35 days. Mice were euthanized, and livers were harvested to count metastatic nodules under a microscope [1] |
| ADME/Pharmacokinetics |
In mice, the bioavailability of a single oral dose of 60 mg/kg Telatinib (BAY 57-9352) was approximately 45%. The plasma half-life was approximately 5.8 hours, and the maximum plasma concentration (Cmax) was reached at 3.2 μg/mL 1.5 hours after administration [2]. In healthy volunteers, the Cmax of oral Telatinib (BAY 57-9352) (900 mg, twice daily) was 1.8 μg/mL, the AUC₀-12h was 12.6 μg·h/mL, and the plasma half-life was 7.2 hours. The drug is mainly metabolized by cytochrome P450 3A4, and 65% of the dose is excreted in feces and 25% in urine within 72 hours [3]. In patients with non-small cell lung cancer (NSCLC), the pharmacokinetic parameters of teratinib (BAY 57-9352) (900 mg, twice daily) were similar to those in healthy volunteers, and no significant accumulation was observed after repeated dosing [4].
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| Toxicity/Toxicokinetics |
Mice treated with Telatinib (BAY 57-9352) at a dose of 60 mg/kg/day for 28 days showed mild weight loss (approximately 9%) and transient diarrhea (15% of animals), but no significant hepatotoxicity or nephrotoxicity. Serum ALT, AST, and creatinine levels were within the normal range [2]. In the phase II clinical trial, the most common adverse reactions to Telatinib (BAY 57-9352) were fatigue (60%), diarrhea (55%), nausea (45%), and hypertension (30%). Grade 3/4 hematologic toxicities included neutropenia (12%) and thrombocytopenia (8%) [3]. The plasma protein binding rate of Telatinib (BAY 57-9352) in human plasma was approximately 94% as determined by balanced dialysis [4].
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| References | |
| Additional Infomation |
Terlatinib belongs to the furanopyridazine class of compounds, with the structure furano[2,3-d]pyridazine, substituted at positions 4 and 7 by (4-chlorophenyl)amino and [2-(methylcarbamoyl)pyridin-4-yl]methoxy, respectively. It is a potent inhibitor of VEGFR2/3, c-Kit, and PDGFRα. It possesses multiple functions including antitumor activity, vascular endothelial growth factor receptor antagonism, EC 2.7.10.1 (receptor protein tyrosine kinase) inhibition, apoptosis induction, and angiogenesis inhibition. It belongs to the monochlorobenzene, aniline, furanopyridazine, aromatic ether, and pyridinecarboxamide classes. Terlatinib is currently being investigated in the clinical trial NCT03817411 (terlatinib in combination with capecitabine/oxaliplatin as first-line treatment for gastric or gastroesophageal junction cancer).
Teratinib (BAY 57-9352) is an oral small molecule inhibitor that exerts antitumor and anti-angiogenic effects by selectively blocking the VEGFR and PDGFR signaling pathways [1]. Teratinib (BAY 57-9352) may enhance antitumor efficacy when used in combination with chemotherapy drugs such as oxaliplatin, providing a potential treatment strategy for advanced colorectal cancer [4]. Teratinib (BAY 57-9352) has shown clinical activity in advanced gastric cancer and non-small cell lung cancer, especially in patients with high VEGF or PDGF expression levels [3]. |
| Molecular Formula |
C20H16CLN5O3
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| Molecular Weight |
409.83
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| Exact Mass |
409.094
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| Elemental Analysis |
C, 58.61; H, 3.94; Cl, 8.65; N, 17.09; O, 11.71
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| CAS # |
332012-40-5
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| Related CAS # |
Telatinib mesylate;332013-26-0
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| PubChem CID |
9808844
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
713.6±60.0 °C at 760 mmHg
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| Flash Point |
385.4±32.9 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.684
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| LogP |
2.53
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
548
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=NC=CC(COC2=NN=C(NC3=CC=C(Cl)C=C3)C4=C2OC=C4)=C1)NC
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| InChi Key |
QFCXANHHBCGMAS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H16ClN5O3/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/h2-10H,11H2,1H3,(H,22,27)(H,24,25)
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| Chemical Name |
4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxymethyl]-N-methylpyridine-2-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.03.00
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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: ≥ 2.08 mg/mL (5.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4400 mL | 12.2002 mL | 24.4004 mL | |
| 5 mM | 0.4880 mL | 2.4400 mL | 4.8801 mL | |
| 10 mM | 0.2440 mL | 1.2200 mL | 2.4400 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 |
| NCT04798781 | Active Recruiting |
Drug: Telatinib Drug: Keytruda |
Hepatocellular Carcinoma Gastric Cancer |
Andrew Hendifar, MD | July 28, 2021 | Phase 2 |
| NCT00952497 | Completed | Drug: Cisplatin, Capecitabine, Telatinib |
Gastric Cancer | ACT Biotech, Inc | June 2009 | Phase 2 |
| 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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