| CAS |
No.874819-74-6 |
| 中文名称 |
托西尼布磷酸盐 |
| 英文名称 |
Toceranib Phosphate |
| 别名 |
SU11654 phosphate;PHA 291639 phosphate; |
| 分子式 |
C22H28FN4O6P |
| 分子量 |
494.46 |
| 溶解性 |
Soluble in Water/DMSO ≥0.1mg/mL |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder: 2-8℃，2 years |
| EC |
EINECS 639-691-4 |
| MDL |
MFCD25372034 |
| SMILES |
CC1=C(NC(=C1C(=O)NCCN2CCCC2)C)/C=C3/C4=C(C=CC(=C4)F)NC3=O.OP(=O)(O)O |
| InChIKey |
AOORBROPMMRREB-HBPAQXCTSA-N |
| InChI |
InChI=1S/C22H25FN4O2.H3O4P/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;1-5(2，3)4/h5-6，11-12，25H，3-4，7-10H2，1-2H3，(H，24，29)(H，26，28);(H3，1，2，3，4)/b17-12-; |
| PubChem CID |
16034840 |
| 靶点 |
PDGFRβ;VEGFR2/KDR/Flk-1 |
| 通路 |
Angiogenesis; Protein Tyrosine Kinase/RTK |
| 背景说明 |
Toceranib phosphate是一种多靶点的受体酪氨酸激酶 (RTK) 抑制剂， 抑制 PDGFRβ 和 Flk-1/KDR。 |
| 生物活性 |
Toceranib phosphate (SU11654 phosphate) is an orally active receptor tyrosine kinase (RTK) inhibitor， and it potently inhibits PDGFR， VEGFR， and Kit with Kis of 5 and 6 nM for PDGFRβ and Flk-1/KDR， respectively. Toceranib phosphate (SU11654 phosphate) has antitumor and antiangiogenic activity， and used in the treatment of canine mast cell tumors .[1-4] |
| In Vitro |
Toceranib phosphate (PHA 291639 phosphate) is a selective inhibitor of the tyrosine kinase activity of several members of the split kinase RTK family， including PDGFR and Flk-1/KDR， with Kis of 5 and 6 nM， respectively[1].
To explore mechanisms of acquired Toceranib (TOC) resistance in canine MCT， three resistant sublines are generated from the Toceranib-sensitive exon 11 ITD c-kit mutant C2 cell line designated TR1， TR2， and TR3. Growth of the parental C2 cells is inhibited by Toceranib in a dose-dependent manner with an IC50 of 50>?1，000 nM). Sensitivity to three other KIT RTK inhibitors is similar to the observed resistance to Toceranib. The parental line as well as all three sublines retains sensitivity to the cytotoxic agents vinblastine (VBL) and CCNU. Following 72 hr culture in the presence of increasing concentrations of Toceranib， treatment na?ve， parental C2 cells detach from the culture flask and become rounded， shrunken， and clumped with increased exposure to Toceranib. In contrast， Toceranib-induced morphologic differences are not identified in the resistant sublines[2]. |
| In Vivo |
Administration of Toceranib phosphate (PHA 291639 phosphate) significantly decreases the number and percentage of Treg in the peripheral blood of dogs with cancer. Dogs receiving Toceranib phosphate (PHA 291639 phosphate) and cyclophosphamide (CYC) demonstrate a significant increase in serum concentrations of IFN-γ， which is inversely correlated with Treg numbers after 6 weeks of combination treatment[3]. |
| 细胞实验 |
The c-kit mutant canine C2 mastocytoma cell line， derived from a spontaneously occurring cutaneous mast cell tumors (MCTs)， is used as the parental cell line. Cells are propagated in RPMI 1640 supplemented with 2 mM L-glutamine， 10% FBS， 100 g/mL Streptomycin， and 100 U/mL Penicillin in a 37°C incubator under a humidified atmosphere of 5% CO2. Toceranib-resistant C2 cells are selected by growing C2 cells in concentrations of Toceranib ranging from 0.02 uM to 0.3 uM and increasing in 0.025-0.05 uM increments. Three independent， Toceranib -resistant sublines are established over a period of 7 months[2]. |
| 动物实验 |
Dogs[3]
Fifteen client-owned dogs with advanced tumors are used. Dogs receive Toceranib at 2.75 mg/kg once every other day. After 2 weeks， oral cyclophosphamide (CYC) is added at 15 mg/m2 daily. Numbers of Treg and lymphocyte subsets are measured in blood by flow cytometry during the 8-week study period. Serum concentrations of IFN-γ are measured by ELISA. |
| 数据来源文献 |
[1]. London CA， et al. Phase I dose-escalating study of SU11654， a small molecule receptor tyrosine kinase inhibitor， in dogs with spontaneous malignancies. Clin Cancer Res. 2003 Jul;9(7):2755-68.
[2]. Halsey CH， et al. Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia?) in canine mast cell tumor. BMC Vet Res. 2014 May 6;10:105.
[3]. Mitchell L， et al. Clinical and immunomodulatory effects of toceranib combined with low-dose cyclophosphamide in dogs with cancer. J Vet Intern Med. 2012 Mar-Apr;26(2):355-62.
[4]. London C， Mathie T， Stingle N， et al. Preliminary evidence for biologic activity of toceranib phosphate (Palladia(?)) in solid tumours. Vet Comp Oncol. 2012;10(3):194-205. |
| 规格 |
5mg 10mg 25mg 50mg 100mg |
| 单位 |
瓶 |
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