PP242 is a first selective inhibitor that targets ATP domain of mTOR. PP242 displays selectivity for mTOR over other PI 3K family kinases (IC50 values are 0.102, 0.408, 1.27, 1.96 and 2.2 μM for p110γ, DNA-PK, p110δ, p110α and p110β respectively). PP242 induced ERK activation in MM cell lines as well as primary cells. PP242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. PP242 was more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, PP242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. PP242 inhibits both S6K and 4EBP1 phosphorylation; activity causes a decrease in cap-dependent protein translation.
|Cell lines||PC-3, SKOV3, 786-O, and U87 cells|
|Preparation method||In vitro proliferation and drug combination experiments.
Cells were seeded in triplicate wells of 96-well flat bottom culture plates for 48 hr in the presence of increasing concentrations of indicated inhibitors. Cell viability and median-effect dose affecting growth (GIC50) was determined using the MTS assay (Cell Titer 96 Aqueous One solution cell proliferation assay kit; Promega). Absorbance values (490 nm) were normalized to controls and expressed as %MTS conversion. Wells lacking cells but with MTS added were used as the zero value when normalizing. For drug combination experiments, a range of fixed ratios of inhibitors was used to assess synergy using the combination index (CI) with CalcuSyn software (Biosoft) according to the median-effect method as previously described 2. For proliferation experiments with PC-3, SKOV3, 786-O, and U87 cells, the CellTiter-Glo Luminesecent reagent (Promega) was used following the manufacturer’s instructions. Quantitation was performed as mentioned above.
|Incubation time||48 h|
|Animal models||xenograft experiments with human Ph+ leukemia|
|Formulation||PEG400 or 5% NMP, 15% PVP, 80% water|
|Dosages||60mg/kg once daily|
|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.
|Solubility||DMSO 60 mg/mL|
The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/eukaryotic translation initiation factor 4E (eIF-4E)/RAF pathway and activation is a mechanism of resistance.
Hoang B, et al. J Biol Chem. 2012 Jun 22;287(26):21796-805. PMID: 22556409.
Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor.
Hoang B, et al. Blood. 2010 Nov 25;116(22):4560-8. PMID: 20686120.
Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor.
Janes MR, et al. Nat Med. 2010 Feb;16(2):205-13. PMID: 20072130.
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