Dovitinib (TKI-258, CHIR-258) (Synonyms: CHIR258, TKI-258) |
| Catalog No.GC13547 |
Dovitinib (TKI-258, CHIR-258) (CHIR-258) is an orally active, potent multi-targeted tyrosine kinase (RTK) inhibitor with IC50s of 1, 2, 36, 8/9, 10/13/8, 27/210 nM for FLT3, c-Kit, CSF-1R, FGFR1/FGFR3, VEGFR1/VEGFR2/VEGFR3 and PDGFRα/PDGFRβ, respectively. Dovitinib (TKI-258, CHIR-258) has potent antitumor activity.
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Cas No.: 405169-16-6
Sample solution is provided at 25 µL, 10mM.
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Dovitinib (TKI258, CHIR-258) is a multitargeted receptor tyrosine kinase inhibitor against FLT3, KIT, FGFR, VEGFR, PDGFRα and PDGFRβ with IC50 of 1 nM, 2 nM, 8-9 nM, 8-13 nM , 210 nM and 27nM, respectively [1].
The viability of ZNF198-FGFR1 or BCR-FGFR1 cells was specifically inhibited by TKI258 with IC50 values of 150 nM or 90 nM. The phosphorylation of ERK and STAT5 genes was inhibited by TKI258 in dose dependent manner. TKI258 also specifically inhibited proliferation and survival of the FGFR1OP2-FGFR1-positive KG1 and KG1A cell lines, increasing levels of apoptosis [2]. In hepatocellular carcinoma (HCC) cells, the combination of TKI258 and tigatuzumab restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced apoptosis. TKI258 inhibited phosphorylation of STAT3 and subsequently reduced the protein levels of Mcl-1, Survivin and Cylcin D1. Co-treatment of TRAIL and TKI258 increased the activity of SHP-1 [3]. Inhibition of FGFR3 with TKI258 decreased waldenstr m macroglobulinemia (WM) cell survival, increased apoptosis, and induced cell cycle arrest. TKI258 reduced the interaction of WM to bone marrow element, and reversed its proliferation. TKI258 had an additive effect with other drugs [4].
In vivo, the combination of tigatuzumab and TKI258 inhibited Huh-7 xenograft tumor growth [3]. TKI258 reduced WM tumor progression [4].
Reference:
[1]. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005 Apr 1;105(7):2941-8.
[2]. Chase A, Grand FH, Cross NC. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007 Nov 15;110(10):3729-34.
[3]. Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, Cheng AL. Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol. 2012 Mar 15;83(6):769-77.
[4]. Azab AK, Azab F, Quang P, Maiso P, Sacco A, Ngo HT, Liu Y, Zhang Y, Morgan BL, Roccaro AM, Ghobrial IM. FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation. Clin Cancer Res. 2011 Jul 1;17(13):4389-99.
| Kinase experiment [1]: | |
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Inhibitory activities |
IC50 values for the inhibition of RTKs by CHIR-258 were determined in a time-resolved fluorescence (TRF) or radioactive format, measuring the inhibition by CHIR-258 of phosphate transfer to a substrate by the respective enzyme. The kinase domains of FGFR3, FGFR1, PDGFR-β and VEGFR1-3 were assayed in 50 mM HEPES (N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid), pH 7.0, 2 mM MgCl2, 10 mM MnCl2, 1 mM NaF, 1 mM dithiothreitol (DTT), 1 mg/mL bovine serum albumin (BSA), 0.25 μM biotinylated peptide substrate (GGGGQDGKDYIVLPI), and 1 to 30 μM adenosine triphosphate (ATP) depending on the Km for the respective enzyme. ATP concentrations were at or just below Km. For c-KIT and FLT3 reactions the pH was raised to 7.5 with 0.2 to 8 μM ATP in the presence of 0.25 to 1 μM biotinylated peptide substrate (GGLFDDPSYVNVQNL). Reactions were incubated at room temperature for 1 to 4 hours and the phosphorylated peptide captured on streptavidin-coated microtiter plates containing stop reaction buffer (25 mM EDTA, 50mM HEPES, pH 7.5). |
| Cell experiment [1]: | |
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Cell lines |
Human multiple myeloma (MM) cell lines and B9 cells |
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Preparation method |
The solubility of this compound in DMSO is >36.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
100 nM CHIR-258; 48-96 h. |
|
Applications |
Dovitinib is a receptor tyrosine kinases inhibitor. Dovitinib selectively inhibits the growth of human myeloma cell lines and B9 cells expressing wild-type (WT) or activated mutant FGFR3. Dovitinib also causes cytostatic and cytotoxic effects and inhibits downstream extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. |
| Animal experiment [1]: | |
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Animal models |
6- to 8-week-old female BNX mice bearing 3 ×107 KMS11 cells. |
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Dosage form |
10, 30, or 60 mg/kg for 21 days by gavage. |
|
Preparation method |
Dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 20 mM. For animal experiments: formulated in 5 mM citrate buffer. |
|
Applications |
Dovitinib causes antitumor effect and inhibits tumor growths by 48%, 78.5%, and 94% in the 10 mg/kg, 30 mg/kg, and 60 mg/kg treatment arms, respectively. Weight loss, as a marker of significant toxicity, is not observed in any of the treatment groups. Dovitinib completely inhibits FGFR3 at the 60 mg/kg dose. CHIR-258 induces both cytostatic and cytotoxic responses. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Trudel S, Li ZH, Wei E, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood, 2005, 105(7): 2941-2948. |
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| Cas No. | 405169-16-6 | SDF | |
| Synonyms | CHIR258, TKI-258 | ||
| Chemical Name | (3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one | ||
| Canonical SMILES | CN1CCN(CC1)C2=CC3=C(C=C2)NC(=C4C(=C5C(=NC4=O)C=CC=C5F)N)N3 | ||
| Formula | C21H21FN6O | M.Wt | 392.43 |
| Solubility | ≥ 36.35mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5482 mL | 12.7411 mL | 25.4823 mL |
| 5 mM | 0.5096 mL | 2.5482 mL | 5.0965 mL |
| 10 mM | 0.2548 mL | 1.2741 mL | 2.5482 mL |
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 29 reference(s) in Google Scholar.)
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