Mubritinib (TAK 165) 366017-09-6

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Molecular Weight:

468.47 Mubritinib (TAK-165) is a Potent Inhibitor of HER2/ErbB2 with IC50 of 6 nM; no activity to EGFR, FGFR, PDGFR, JAK1, Src and Blk. Phase 1.


Biological Activity


Mubritinib displays > 4000-fold selectivity over other tyrosine
kinases, such as EGFR, FGFR, PDGFR, Jak1, Src and Blk. Mubritinib 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. Mubritinib 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.
Mubritinib 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.


Mubritinib 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 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, as compared with Herceptin (20 mg/kg) which is ineffective
to UMUC-3 tumor growth.






Inhibition of HER2/erbB2 tyrosine kinase activity


BT-474 cells are seeded on 24-well plates and cultured overnight.
Mubritinib 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 Mubritinib
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.


Method


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.

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Product Categories : Protein Tyrosine Kinase > HER2 Inhibitor