product name Mubritinib (TAK 165)
Description: Mubritinib (also known as TAK-165) is a potent inhibitor of HER2/ErbB2 with IC50 of 6 nM in BT-474 cell; it has no activity to EGFR, FGFR, PDGFR, JAK1, Src and Blk in BT-474 cell line. It completed phase I clinical trials (may be discontinued since 2008). Mubritinib(TAK 165) is a potent EGFR, HER2 and p34cdc2 inhibitor with IC50 of 6 nM and 0.2 µM, respectively. Mubritinib(TAK 165) also inhibits p33cdk2 and p33cdk5. Mubritinib(TAK 165) displays > 4000-fold selectivity over EGFR, FGFR, PDGFR, JAK1 and Src. Mubritinib(TAK 165) exhibits potent antiproliferative effects in ErbB2-overexpressing cancer cell lines (IC50 = 5 nM in BT474 breast cancer cells) and significantly inhibits bladder, breast and prostate cancer xenograft growth in vivo.
References: Int J Urol. 2006 May;13(5):587-92.
468.47
Formula
C25H23F3N4O2
CAS No.
366017-09-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
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
Synonyms
TAK-165
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19426299
| In Vitro |
In vitro 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. Kinase Assay: 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: Cells (BT474, HT1376, UMUC-3, T24, ACHN, DU-145, PC-3, LN-REC4, and LNCaP 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. |
|---|---|
| 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. |
| Animal model | 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 |
| Formulation & Dosage | Dissolved in DMSO; 10 or 20 mg/kg/day; p.o. |
| References | Int J Urol. 2006 May;13(5):587-92. |
