mTOR inhibitor-3

mTOR inhibitor-3 is a remarkably selective mTOR inhibitor with a K i of 1.5 nM. mTOR inhibitor-3 suppresses mTORC1 and mTORC2 in cellular and in vivo pharmacokinetic (PK)/pharmacodynamic (PD) experiments. In Vitro mTOR inhibitor-3 (Compound 12i) inhibits mTOR with a K i of 1.5 nM, 500-fold selectivity over closely related PI3 kinases. mTOR inhibitor-3 inhibits NCI-PC3 and MCF7neo/Her2 cells proliferation with IC 50 s of 150 nM and 57 nM, respectively. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo mTOR inhibitor-3 (Compound 8h) has high free plasma clearance in both mice (1818 mL/min/kg) and rats (1538 mL/min/kg in rat) . mTOR inhibitor-3 (Compounds 12i) is selected for this study due to its potency, selectivity, and favorable mouse PK profile. Plasma levels of mTOR inhibitor-3 6 h following oral administration in PC3 tumor-bearing mice along with the fold decreases of phosphorylated mTORC1 and -2 substrates relative to time-matched vehicle controls. mTOR inhibitor-3 has moderate terminal elimination half-life (t 1/2 =1.7 h for mouse(1 mg/kg, iv)). mTOR inhibitor-3 achieves tumor stasis at the highest 200 mg/kg/day dose examined, which appears to also be approaching the limit of tolerability for this molecule. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal administration Mice Human prostate cancer NCI-PC3 cells are implanted subcutaneously into the right hind flanks of female NCR nude mice (5×10 6 cells in 100 μL of Hank’s balanced salt solution). Tumors are monitored until they reach a mean tumor volume of approximately 500 mm 3 . Then similarly sized tumors are randomly assigned to groups (n=4). Compounds are formulated as suspensions in 0.5% methylcellulose/0.2% Tween 80 (MCT) and dosed orally at 25, 50, and 100 mg/kg (100 μL dose/25 g animal). Tumor and plasma samples are harvested at 1, 6, and 10 h postdose. aladdin has not independently confirmed the accuracy of these methods. They are for reference only.

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