WYE-354 is a potent and ATP competitive inhibitor of mTOR (IC50 = 5 nM), with significant selectivity over PI3K isofoms (>100-fold). WYE-354 is equally potent against mTORC1 and mTORC2 activities in HEK293 immune complex kinase assays using S6K and Akt as the respective substrate (IC50 <200 nM) and effectively blocks cellular phosphorylation of S6K on T389 and Akt on S473 both in cultures and in a murine xenograft model, resulting in a significant suppression of PC3MM2-derived tumor growth (by 86% on day 7; 50 mg/kg, i.p twice per day) in vivo.
|Source||Oncotarget (2015). Figure 1. WYE-354|
|Cell Lines||Western blot analysis|
|Incubation Time||24, 48, and 72 h|
|Results||WYE-354 significantly reduced cell viability starting at a 1 μM concentration after a 24 hours exposure, in both studied cell lines|
|Cell lines||Cell lines of Rat1, HEK293, MDA-MB-361, MDA-MB-468, MDA-MB-231, LNCap, DU145, U87MG, A498, HCT116, and HT29|
|Preparation method||Tumor cell growth assays.|
|Concentrations||0~100 μ M|
|Incubation time||3 days|
|Animal models||PC3MM2 tumors xenograft in BALB/c nu/nu female mice|
|Formulation||formulated in 5% ethanol, 5% polysorbate 80, 5% polyethylene glycol-400|
|Dosages||a single i.p. injection with 50 mg/kg|
|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.
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.
Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin.
Yu K et al. Cancer Res. 2009 Aug 1;69(15):6232-40. PMID: 19584280.
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Zotarolimus (ABT-578) is an analogue of rapamycin, and inhibits FKBP-12 binding with IC50 of 2.8 nM.
LY303511 is a structural analogue of LY294002, which does not inhibit PI3K, increased homotypic GJIC.
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