Mubritinib (TAK 165)

Alias: TAK-165; Mubritinib; TAK 165; TAK165
Cat No.:V0581 Purity: ≥98%
Mubritinib (formerly also known as TAK165; TAK-165) is a novel, potent, selective and investigational inhibitor of HER2/ErbB2 with potential anticancer activity.
Mubritinib (TAK 165) Chemical Structure CAS No.: 366017-09-6
Product category: HER-2
This product is for research use only, not for human use. We do not sell to patients.
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Product Description

Mubritinib (formerly also known as TAK165; TAK-165) is a novel, potent, selective and investigational inhibitor of HER2/ErbB2 with potential anticancer activity. It has no effect on EGFR, FGFR, PDGFR, JAK1, Src, or Blk in BT-474 cells, but it inhibits HER2/ErbB2 with an IC50 of 6 nM in these cells. Takeda developed it and it has successfully completed phase I clinical trials for the treatment of cancer (though it may have been discontinued since December 2008). Mubritinib exhibits significant in vivo antitumor efficacy against bladder, breast, and prostate cancer xenografts in vivo, as well as strong anti-proliferative activity against ErbB2-overexpressing cancer cell lines, with an IC50 of 5 nM in BT474 breast cancer cells.

Biological Activity I Assay Protocols (From Reference)
Targets
HER2 (IC50 = 6 nM)
ln Vitro

Mubritinib (TAK-165) has an IC50 of 6 nM for HER2 tyrosine kinase inhibition and does not inhibit tyrosine kinase of other types up to 25 000 nM. In HER2 strongly expressing cells, such as the BT474 breast cancer cell line, mubritinib inhibits HER2 phosphorylation and its downstream Akt and MAPK. Each cell line's HER2 level determines its sensitivity to mbritinib. Particularly, PC-3 cells, which express HER2 very weakly, are less sensitive (IC50=4.62 μM) than BT474 cells, which over-express HER2 strongly and are highly sensitive (IC50=0.005 μM). However, over-expressed EGFR cells in HT1376 and ACHN displayed high IC50 (IC50>25 μM)[1].

ln Vivo
Mubritinib suppresses LN-REC4 xenograft with a tumor volume ratio of 26.5% between treatment and control. Oral administration of Mubritinib (10 or 20 mg/kg per day) significantly inhibits the growth of UMUC-3 and ACHN xenografts with treatment/control tumor volume ratio of 22.9% and 26%, respectively, compared with Herceptin (20 mg/kg), which is ineffective to UMUC-3 tumor growth, despite the fact that it is ineffective to inhibit the growth of UMUC-3 and ACHN cells in vitro (IC50s of 1.812 and >25 μM, respectively).
Enzyme Assay
On 24-well plates, BT-474 cells are plated and allowed to grow overnight. Then, different doses of mubritinib are added. The cells are harvested directly into 200 μL of sodium dodecyl sulfate (SDS)-sample buffer after two hours of incubation. On a 7.5% to 15% gradient SDS–polyacrylamide gel electrophoresis (PAGE), aliquots with equal volumes of total cell extract are run. After the electrophoresis process, proteins are blotted onto a PVDF membrane using a primary antibody specific to the desired western blot analysis. A technique known as enhanced chemiluminescent (ECL) detection is used to detect proteins. The LAS-1000 plus lumino-image analyzer measures the degree of tyrosine phosphorylation of HER2/erbB2. Mubritinib's 50% inhibitory concentration (IC50) on HER2/erbB2 phosphorylation is determined by analyzing a dose-response curve produced by least-squares linear regression of the response with SAS software.
Cell Assay
Cells are seeded into 6-well plates and cultured overnight. Mubritinib is then added at various concentrations, and the cells are treated continuously for 72 hours. After the incubation period, cells are counted for the measurement of antiproliferative activity.
Animal Protocol
Mice: Implantation of 50% Matrigel solution is done on UMUC-3 and LN-REC4 cells. The mice receive oral treatment twice daily for 14 days, either with vehicle (control) or 10 or 20 mg/kg of mubritinib per day, after the tumor volume reaches 200–300 mm3 in LN-REC4 and UMUC-3 cells and 100–200 mm3 in ACHN[1].
References

[1]. Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo. Int J Urol. 2006 May;13(5):587-92.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C25H23F3N4O2
Molecular Weight
468.47
Exact Mass
468.18
Elemental Analysis
C, 64.10; H, 4.95; F, 12.17; N, 11.96; O, 6.83
CAS #
366017-09-6
Appearance
white solid powder
SMILES
C1=CC(=CC=C1CCCCN2C=CN=N2)OCC3=COC(=N3)/C=C/C4=CC=C(C=C4)C(F)(F)F
InChi Key
ZTFBIUXIQYRUNT-MDWZMJQESA-N
InChi Code
InChI=1S/C25H23F3N4O2/c26-25(27,28)21-9-4-20(5-10-21)8-13-24-30-22(18-34-24)17-33-23-11-6-19(7-12-23)3-1-2-15-32-16-14-29-31-32/h4-14,16,18H,1-3,15,17H2/b13-8+
Chemical Name
4-[[4-[4-(triazol-1-yl)butyl]phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole
Synonyms
TAK-165; Mubritinib; TAK 165; TAK165
HS Tariff Code
2934.99.9001
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)
Solubility Data
Solubility (In Vitro)
DMSO: ~13 mg/mL (~27.7 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
1% DMSO+30% polyethylene glycol+1% Tween 80: 5mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1346 mL 10.6730 mL 21.3461 mL
5 mM 0.4269 mL 2.1346 mL 4.2692 mL
10 mM 0.2135 mL 1.0673 mL 2.1346 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.

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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.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00034281 Completed Drug: TAK-165 Breast Neoplasm
Lung Neoplasm
Takeda June 2002 Phase 1
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