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Purity: ≥98%
Toceranib (formerly known as PHA-291639, or SU-11654) is an inhibitor of receptor tyrosine kinase (RTK) with anticancer activities. It inhibits Flk-1/KDR and PDGFRβ with Ki values of 6 nM and 5 nM, respectively. Toceranib (brand name: Palladia) has been authorized for use as a veterinary medication to treat canine mast cell tumors, also known as mastocytomas. Toceranib may also have an anti-angiogenic effect, but its main mechanism of action is probably inhibition of kit tyrosine kinase. is an anticancer and antineoplastic drug used to treat canine mast cell tumors.
| Targets |
PDGFRβ (Ki = 5 nM); Flk-1 (Ki = 6 nM)
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| ln Vitro |
Toceranib (SU11654) is a selective inhibitor of PDGFR and Flk-1/KDR tyrosine kinase activity, as well as other members of the split kinase RTK family, with a Kis of 5 and 6 nM, respectively[1].
The Toceranib-sensitive exon 11 ITD c-kit mutant C2 cell line is used to create three resistant sublines, TR1, TR2, and TR3, which are then used to investigate the mechanisms of acquired Toceranib (TOC) resistance in canine MCT. With an IC50 of less than 10 nM, toceranib inhibits the growth of the parental C2 cells in a dose-dependent manner. Conversely, sublines TR1, TR2, and TR3 exhibit resistance against Toceranib's inhibition (IC50>1,000 nM). Similar to the reported resistance to toceranib, sensitivity to three additional KIT RTK inhibitors is seen. Vinblastine (VBL) and CCNU are cytotoxic agents that still cause sensitivity in the parental line and all three sublines. After being cultured for 72 hours in the presence of increasing Toceranib concentrations, treatment-naïve parental C2 cells separate from the culture flask and, as Toceranib exposure increases, they become clumped, shrunken, and rounded. In contrast, it is not possible to identify morphologic differences induced by ceranib in the resistant sublines[2]. |
| ln Vivo |
Fifty-seven dogs with a variety of cancers were enrolled; of these, 10 experienced progressive disease within the first 3 weeks. Measurable objective responses were observed in 16 dogs (including 6 complete responses), primarily in mast cell tumors (n = 11), mixed mammary carcinomas (n = 2), soft tissue sarcomas (n = 2), and multiple myeloma (n = 1), for an overall response rate of 28% (16 of 57). Stable disease of sufficient duration to be considered clinically meaningful (>10 weeks) was seen in an additional 15 dogs, for a resultant overall biological activity of 54% (31 of 57). Conclusions: This study provides the first evidence that p.o. administered kinase inhibitors can exhibit activity against a variety of spontaneous malignancies. Given the similarities of canine and human cancers with regard to tumor biology and the presence of analogous RTK dysregulation, it is likely that such agents will demonstrate comparable antineoplastic activity in people.[1]
Administration of toceranib significantly decreased the number and percentage of Treg in the peripheral blood of dogs with cancer. Dogs receiving toceranib and CYC demonstrated a significant increase in serum concentrations of IFN-γ, which was inversely correlated with Treg numbers after 6 weeks of combination treatment. Conclusions: In addition to antitumor effects, these data support further investigations into the immunomodulatory effects of toceranib, administered alone or in combination with CYC in dogs with cancer.[3] The amount and proportion of Treg in cancer-stricken dogs' peripheral blood dramatically decrease after toceranib administration. After 6 weeks of combination therapy, dogs receiving toceranib and cyclophosphamide (CYC) show a significant increase in serum concentrations of IFN-γ, which is inversely correlated with Treg numbers[3]. |
| Enzyme Assay |
Toceranib (SU11654) is a selective inhibitor of PDGFR and Flk-1/KDR tyrosine kinase activity, as well as other members of the split kinase RTK family, with a Kis of 5 and 6 nM, respectively. For PDGFR and Flk-1/KDR, two members of the split kinase RTK family, toceranib (SU11654) selectively inhibits tyrosine kinase activity at 5 and 6 nM, respectively.
The canine C2 mastocytoma cell line contains an activating mutation in c-kit. Three Toceranib (TOC)-resistant C2 sublines (TR1, TR2, TR3) were established over seven months by growing cells in increasing concentrations of TOC. TOC inhibited KIT phosphorylation and cell proliferation in a dose-dependent manner in the treatment-naïve, parental C2 line (IC50 < 10 nM). In contrast, the three sublines were resistant to growth inhibition by TOC (IC50 > 1,000 nM) and phosphorylation of the KIT receptor was less inhibited compared to the TOC-sensitive C2 cells. Interestingly, sensitivity to three structurally distinct KIT RTK inhibitors was variable among the sublines, and all 3 sublines retained sensitivity to the cytotoxic agents vinblastine and lomustine. Sequencing of c-kit revealed secondary mutations in the juxtamembrane and tyrosine kinase domains of the resistant sublines. These included point mutations in TR1 (Q574R, M835T), TR2 (K724R), and TR3 (K580R, R584G, A620S). Additionally, chronic TOC exposure resulted in c-kit mRNA and KIT protein overexpression in the TOC-resistant sublines compared to the parental line. C2, TR1, TR2, and TR3 cells demonstrated minimal P-glycoprotein (P-gp) activity and no functional P-gp. Conclusions: This study demonstrates the development of an in vitro model of acquired resistance to targeted therapy in canine MCTs harboring a c-kit-activating mutation. This model may be used to investigate the molecular basis of and strategies to overcome TOC resistance [2].
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| Cell Assay |
The cells of BR, C2, and P815 were counted and then resuspended in complete medium in 24-well plates at a concentration of 0.5 × 106 cells/well (for BR and C2) or 0.25 × 106 cells/well (for P815). Cells were left untreated, or SU11652, SU11654, or SU11655 was added to a final concentration of 0.01 to 1 μM. After being cultured for 24, 48, and 72 hours, cells were taken out and counted to find out how many cells survived.
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| Animal Protocol |
Dogs; Fifteen client-owned dogs with advanced tumors are used. Toceranib is given to dogs once every other day at a dosage of 2.75 mg/kg. Oral cyclophosphamide (CYC) is added at a daily dose of 15 mg/m2 following a 2-week period. Throughout the eight-week study period, flow cytometry is used to quantify the number of Treg and lymphocyte subsets in blood. ELISA is used to gauge IFN- concentrations in serum.
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| References |
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| Additional Infomation |
See also: Toceranib Phosphate (has salt form).
Drug Indication Treatment of non-resectable Patnaik grade-II (intermediate-grade) or -III (high-grade), recurrent, cutaneous mast-cell tumours in dogs. |
| Molecular Formula |
C22H25FN4O2
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|---|---|
| Molecular Weight |
396.47
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| Exact Mass |
396.196
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| Elemental Analysis |
C, 66.65; H, 6.36; F, 4.79; N, 14.13; O, 8.07
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| CAS # |
356068-94-5
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| Related CAS # |
Toceranib phosphate;874819-74-6;Toceranib-d8;1795134-78-9
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| PubChem CID |
5329106
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| Appearance |
Yellow to orange solid powder
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| LogP |
3.686
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
663
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=C([H])C2=C(C=1[H])/C(/C(N2[H])=O)=C(\[H])/C1=C(C([H])([H])[H])C(=C(C([H])([H])[H])N1[H])C(N([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O
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| InChi Key |
SRSGVKWWVXWSJT-ATVHPVEESA-N
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| InChi Code |
InChI=1S/C22H25FN4O2/c1-13-19(12-17-16-11-15(23)5-6-18(16)26-21(17)28)25-14(2)20(13)22(29)24-7-10-27-8-3-4-9-27/h5-6,11-12,25H,3-4,7-10H2,1-2H3,(H,24,29)(H,26,28)/b17-12-
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| Chemical Name |
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide
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| Synonyms |
SU-11654; PHA291639; SU 11654; PHA 291639; SU11654; PHA-291639; Toceranib; Toceranib [USAN]; (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide; (Z)-5-(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-N-[2-(1-pyrrolidinyl)ethyl]-1H-pyrrole-3-carboxamide; Trade name: Palladia
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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) |
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 | 2.5223 mL | 12.6113 mL | 25.2226 mL | |
| 5 mM | 0.5045 mL | 2.5223 mL | 5.0445 mL | |
| 10 mM | 0.2522 mL | 1.2611 mL | 2.5223 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.
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