Mubritinib

Mubritinib, also known as TAK-165, is a protein kinase inhibitor which was under development by Takeda for the treatment of cancer. 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.

Product information

CAS Number: 366017-09-6

Molecular Weight: 468.47

Formula: C25H23F3N4O2

Synonym:

TAK 165

TAK-165

TAK165

Chemical Name: (E)-4-((4-(4-(1H-1, 2, 3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole

Smiles: FC(F)(F)C1=CC=C(C=C1)/C=C/C1=NC(COC2C=CC(CCCCN3C=CN=N3)=CC=2)=CO1

InChiKey: ZTFBIUXIQYRUNT-MDWZMJQESA-N

InChi: 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+

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO 93 mg/mL (198.52 mM)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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.

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.

References:

1. Nagasawa J, et al. Int J Urol, 2006, 13(5), 587-592.

Products are for research use only. Not for human use.