Mubritinib (TAK 165)

 

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Biological Activity

Description	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.
Targets	ErbB2
IC50	6 nM [1]
In vitro	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. [1]
In vivo	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. [1]
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

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.

Cell Assay: ^[1]

Cell lines	BT474, HT1376, UMUC-3, T24, ACHN, DU-145, PC-3, LN-REC4, and LNCaP cells
Concentrations	Dissolved in DMSO, final concentrations ~50 mM
Incubation Time	72 hours
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.

Animal Study: ^[1]

Animal Models	Athymic nude mice (BALB/c nu/nμ) and SCID mice (C.B.-17 Scid/Scid) are implanted subcutaneously with UMUC-3, LN-REC4 or ACHN cells
Dosages	10 or 20 mg/kg/day
Administration	Orally twice daily
Solubility	1% DMSO/30% polyethylene glycol/1% Tween 80, 5 mg/mL

1

References

Chemical Information

Download Mubritinib (TAK 165) SDF

Chemical Name	(E)-1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.46847	4.6847	9.3694	-

Product Citations (2)

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  The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI-resistant NSCLC cells. [Chen MC, et al. Cell Death Dis 2013;4:e810]

  
  PubMed: 24052078


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  A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets. [Uitdehaag JC, et al. Br J Pharmacol 2012;166(3):858-76]

  
  PubMed: 22250956