KU-0063794 is a potent and selective mTOR inhibitor with IC50 values of approximately 10 nM for mTORC1 and mTORC2.But KU-0063794 does not inhibit the activity of 76 other protein kinases and seven lipid kinases at 1000-fold higher concentrations. KU-0063794 also inhibited growth of T47D breast cancer cells with a GI50 of 0.35 µM.
|Source||J Invest Dermatol (2013). Figure 1. KU-0063794|
|Method||In-Cell Western Blotting|
|Cell Lines||Primary KFs cells|
|Incubation Time||24 h|
|Results||Both AZ compounds showed a significant (P<0.01) reduction of p-mTOR, Rictor, and Raptor immunoreactivity|
|Cell lines||MEFs cell line|
|Preparation method||Cell growth. MEFs were seeded in 24-well plates (20000 cells per 1.91 cm2 well) and grown overnight in the presence of 10% foetal bovine serum. Cells were then treated in the presence or absence or rapamycin or Ku-0063794 and the medium was changed every 24 h with freshly dissolved inhibitors. Every 24 h of treatment, cells were washed once with PBS, and fixed in 4% (v/v) paraformaldehyde in PBS for 15 min. After washing once with water, the cells were stained with 0.1% Crystal Violet in 10% ethanol for 20 min and washed three times with water. Crystal Violet was extracted from cells with 0.5 ml of 10% (v/v) ethanoic (acetic) acid for 20 min. The eluate was then diluted 1:10 in water, and absorbance at 590 nm was quantified.|
|Incubation time||1, 2 or 3 days|
|Animal models||Xenograft Model of RCC|
|Formulation||solubilized in one part DMSO and then diluted (200 µg/100 µl) with 4 parts PEG1500 (50% (w/v) in 75 mM Hepes, pH 8.0, Roche Applied Science)|
|Dosages||8 mg/kg once daily (five days a week)|
|Administration||intraperitoneal (IP) injection|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclinical renal cell carcinoma models.
Zhang H, et al. PLoS One. 2013;8(1):e54918. PMID: 23349989.
Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin.
Wahdan-Alaswad RS et al. Mol Cancer Res. 2012 Jun;10(6):821-33. PMID: 22452883.
Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR).
García-Martínez JM et al. Biochem J. 2009 Jun 12;421(1):29-42. PMID: 19402821.
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