Mubritinib (TAK 165)

Athymic nude mice (BALB/c nu/nu) and SCID mice (C.B.-17 Scid/Scid) are implanted subcutaneously with UMUC-3, LN-REC4 or ACHN cells

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

Dissolved in DMSO, final concentrations ca.50 mM

10 or 20 mg/kg/day

6 nM [1], 6 nM [1], 6 nM [1], 6 nM [1], 6 nM [1], 6 nM [1]

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 uM, 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]

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 uL). 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.

468, 47

DMSO 13 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL