Home Protein Tyrosine Kinase HER2 inhibitor Mubritinib (TAK 165)

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Mubritinib (TAK 165) HER2 inhibitor

Cat.No.S2216

Mubritinib (TAK-165) is a potent inhibitor of HER2/ErbB2 with IC50 of 6 nM in BT-474 cell; this compound shows no activity to EGFR, FGFR, PDGFR, JAK1, Src and Blk in the same cell line.
Mubritinib (TAK 165) HER2 inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 468.47

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Quality Control

Batch: Purity: 99.94%
99.94

Solubility

In vitro
Batch:

DMSO : 13 mg/mL (27.74 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 468.47 Formula

C25H23F3N4O2

 Storage (From the date of receipt)
CAS No. 366017-09-6 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles C1=CC(=CC=C1CCCCN2C=CN=N2)OCC3=COC(=N3)C=CC4=CC=C(C=C4)C(F)(F)F

Mechanism of Action

Targets/IC50/Ki
HER2/ErbB2
(BT-474 cells)
6.0 nM
In vitro

Mubritinib (TAK 165) displays > 4000-fold selectivity over other tyrosine kinases, such as EGFR, FGFR, PDGFR, Jak1, Src and Blk. It even at low concentration of 0.1 μM significantly blocks HER2 phosphorylation, leading to the downregulation of PI3K-Akt and MAPK pathway in cell line BT474 with high level of HER2. This compound not only exhibits highly potent antiproliferative effect in ErbB2-overexpressing cancer cell line BT474 with an IC50 of 5 nM, but also displays marked antiproliferative effects in cell lines with HER2 expressed weakly with IC50 of 53 nM, 90 nM and 91 nM for LNCaP, LN-REC4 and T24, respectively. It displays no inhibitory activities against PC-3 cells with HER2 expressed very faintly with IC50 of 4.62 μM, as well as EGFR-overexpressing HT1376 and ACHN cell lines with IC50 of >25 μM.

Kinase Assay
Inhibition of HER2/erbB2 tyrosine kinase activity
BT-474 cells are seeded on 24-well plates and cultured overnight. Mubritinib (TAK 165) is then added at various concentrations. After incubation for 2 hours, the cells are harvested directly into sodium dodecyl sulfate (SDS)-sample buffer (200 μL). Aliquots containing equal amounts of total cell extract are run on 7.5% to 15% gradient SDS–polyacrylamide gel electrophoresis (PAGE). Following electrophoresis, proteins are transferred onto a polyvinylidene fluoride (PVDF) membrane, for western blot analysis using a relevant primary antibody. Detection of protein is accomplished by an enhanced chemiluminescent (ECL) detection method. The extent of tyrosine phosphorylation of HER2/erbB2 is measured by the LAS-1000 plus lumino-image analyser. The concentration of this compound that inhibits HER2/erbB2 phosphorylation by 50% (IC50) is calculated from a dose–response curve generated by least-squares linear regression of the response using SAS software.
In vivo

Mubritinib (TAK 165) significantly inhibits LN-REC4 xenograft with treatment/control tumor volume ratio of 26.5%. Although ineffective to inhibit the growth of UMUC-3 and ACHN cells in vitro (IC50s of 1.812 and >25 μM, respectively), oral administration of this compound (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, as compared with 20 mg/kg which is ineffective to UMUC-3 tumor growth.

References

Applications

Methods Biomarkers Images PMID
Western blot pERK / ERK / pAKT / AKT / p-STAT3 / STAT3 / pHER2 / HER2 c-myc / p21 / p27
S2216-WB1
25407459
Growth inhibition assay Cell viability
S2216-viability1
25407459

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00034281 Completed
Breast Neoplasm|Pancreatic Neoplasm|Lung Neoplasm|Ovarian Neoplasm|Renal Neoplasm
Takeda
 June 2002 Phase 1

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