Torkinib (PP242)

Catalog No.S2218
5 5 11 Product Citations

Torkinib (PP242) is a selective mTOR inhibitor with IC50 of 8 nM; targets both mTOR complexes with >10- and 100-fold selectivity for mTOR than PI3Kδ or PI3Kα/β/γ, respectively.

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Torkinib (PP242) Chemical Structure

Torkinib (PP242) Chemical Structure
Molecular Weight: 308.34

Validation & Quality Control

Customer Reviews(7)

Quality Control & MSDS

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Product Description

Biological Activity

Description Torkinib (PP242) is a selective mTOR inhibitor with IC50 of 8 nM; targets both mTOR complexes with >10- and 100-fold selectivity for mTOR than PI3Kδ or PI3Kα/β/γ, respectively.
Targets mTOR [1] p110δ [1] DNA-PK [1] PDGFR [1] Hck [1]

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IC50 8 nM 0.10 μM 0.41 μM 0.41 μM 1.2 μM
In vitro PP242 exhibits potent selectivity for mTOR over other PI3K family kinases such as p110α, p110β, p110γ, p110δ, and DNA-PK with IC50 of 1.96 μM, 2.2 μM, 1.27 μM, 0.102 μM, and 0.408 μM, respectively. PP242 displays some inhibitory activity against Ret, PKCα, PKCβ, and JAK2, while exhibits remarkable selectivity against 215 other protein kinases. Unlike rapamycin, PP242 inhibits both mTORC1 and mTORC2. In BT549 cells, PP242 treatment (0.04-10 μM) inhibits the phosphorylation of Akt, the mTOR substrate p70S6K, and its downstream target S6 in a dose-dependent manner. [1] PP242 potently inhibits PKCα with IC50 of 49 nM. Low concentrations of PP242 inhibit the phosphorylation of Akt S473 and higher concentrations partially inhibit Akt T308-P in addition to S473-P. As PP242 is a more effective mTORC1 inhibitor than rapamycin, PP242 inhibits the proliferation of primary MEFs, and the phosphorylation of 4EBP1 at T36/45 and S65, more potently than rapamycin. PP242 but not rapamycin potently inhibits cap-dependent translation, by causing a higher level of binding between 4EBP1 and eIF4E than rapamycin. [2] PP242 potently inhibits the proliferation of p190-transformed murine BM, SUP-B15, and K562 cells with GI50 of 12 nM, 90 nM, and 85 nM, respectively. PP242 also inhibits the growth of solid tumor cell lines such as SKOV3, PC3, 786-O, and U87 with GI50 of 0.49 μM, 0.19 μM, 2.13 μM, and 1.57 μM, respectively. [3] PP242 is also more effective than rapamycin in achieving cytoreduction and apoptosis in multiple myeloma (MM) cells. [4]
In vivo Administration of PP242 is able to completely inhibit the phosphorylation of Akt at S473 and T308 in fat and liver of mice. PP242 only partially inhibits the phosphorylation of Akt in skeletal muscle and is more effective at inhibiting the phosphorylation of T308 than S473, despite able to fully inhibit the phosphorylation of 4EBP1 and S6. [2] Oral administration PP242 potently delays the leukemia onset in the mice model, and induces leukemia regression by inhibiting mTORC2 and mTORC1 activation that correlates with loss in cell size. [3] PP242 treatment potently inhibits the growth of 8226 cells in mice. [4]
Features One of the first selective inhibitors that targets ATP domain of mTOR.

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro mTOR (FRAP1) kinase assay Recombinant mTOR is incubated with PP242 at 2-fold dilutions over a concentration range of 50-0.001 μM in an assay containing 50 mM HEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 0.01% Tween, 10 μM ATP (2.5 μCi of γ-32P-ATP), and 3 μg/mL BSA. Rat recombinant PHAS-1/4EBP1 (2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1 M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging. IC50 value is calculated by fitting the data to a sigmoidal dose-response curve using the Prism software package.

Cell Assay: [2]

Cell lines MEFs
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 72 hours
Method Cells are treated with increasing concentrations of PP242 for 72 hours in 96-well plates. After 72 hours of treatment, 10 μL of 440 μM resazurin sodium salt is added to each well, and after 18 hours, the florescence intensity in each well is measured using a top-reading florescent plate reader with excitation at 530 nm and emission at 590 nm.

Animal Study: [3]

Animal Models Syngeneic (Balbc/J) mice with mouse p190-transformed BM cells to initiate leukemia, and female NSG mice injected (i.v.) with SUP-B15ffLuc cells or human Ph+ leukemia
Formulation Dissolved in PEG400 (Carbowax polyethylene glycol)
Dosages ~60 mg/kg/day
Administration Oral gavage
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Apsel B, et al. Nat Chem Biol, 2008, 4(11), 691-699.

[2] Feldman ME, et al. PLoS Biol, 2009, 7(2), 0371-0383.

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Chemical Information

Download Torkinib (PP242) SDF
Molecular Weight (MW) 308.34
Formula

C16H16N6O

CAS No. 1092351-67-1
Storage 3 years -20℃Powder
6 months-80℃in solvent (DMSO, water, etc.)
Synonyms
Solubility (25°C) * In vitro DMSO 62 mg/mL (201.07 mM)
Water <1 mg/mL (<1 mM)
Ethanol 18 mg/mL (58.37 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol

Research Area

Customer Reviews (7)


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Rating
Source Autophagy 2012 8(6), 903-14. Torkinib (PP242) purchased from Selleck
Method Immunofluorescence
Cell Lines ARPE-19 cells
Concentrations 1 uM
Incubation Time 2 h
Results It hypothesized that MTORC1 might regulate the distribution and activation of TFEB. To test this possibility we infected ARPE-19 cells with adenovirus expressing TFEB-Flag and treated the cells with PP242. As predicted, PP242 rapidly induced nuclear translocation of TFEB.

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Rating
Source Autophagy 2012 8(6), 903-14. Torkinib (PP242) purchased from Selleck
Method Immunoblotting
Cell Lines HeLa cells
Concentrations 1 uM
Incubation Time 2 h
Results Treatment of cells with the MTOR catalytic inhibitors LY294002, wortmannin or PP242 induced a significant accumulation of TFEB in the nucleus in almost 100% of the cells (97.08% SD ?0.87, n = 308 for LY294002; 95.46% SD ?0.5, n = 309 for wortmannin; 92.2% SD ?1.31, n = 312 for PP242).

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Rating
Source Cancer Res 2013 73(11), 3402-11. Torkinib (PP242) purchased from Selleck
Method Immunoblotting
Cell Lines PC3-LN4 cells
Concentrations 2 uM
Incubation Time 24 h
Results To further define the role of cap-dependent translation in the mechanism of action of this agent, GSK690693 was combined with two potent inhibitors of mTORC1/mTORC2 and thus cap-dependent translation, PP242 and AZD8055. PP242 and AZD8055 in combination with GSK690693 resulted in reduced phosphorylation of 4E-BP1, and increased eIF2α phosphorylation compared to GSK690693 alone, suggesting inhibition of 5′-cap dependent translation.

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Rating
Source Mol Cancer Ther 2014 13(1), 37-48. Torkinib (PP242) purchased from Selleck
Method Assays for chromosome spreading
Cell Lines CSCs<sup>+24/44/ESA</sup>
Concentrations 1 uM
Incubation Time 72 h
Results In this case, BMS-777607 at 5 umol/L is required in combination with 1 umol/L AZD8055 or PP242 to achieve the significant reduction of CSCs+24/44/ESA viability. Again, it found that BMS-777607 in combination with AZD8055 or PP242 decreased the percentages of CSCs+24/44/ESA-derived polyploid cells.

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Rating
Source Mol Cell Biol 2014 34(13), 2517-32. Torkinib (PP242) purchased from Selleck
Method Immunoblotting
Cell Lines HeLa cells
Concentrations 1 uM
Incubation Time 3 h
Results Treatment of HeLa cells with the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway inhibitor BEZ235, PP242, or AZD8055 blocked the phosphorylation of eIF4B S422 but had no effect on S406 phosphorylation. PP242, BEZ235, and, to a lesser extent, MK2206 inhibited eIF4B S422 phosphorylation.

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Rating
Source Dr. Zhang of Tianjin Medical University. Torkinib (PP242) purchased from Selleck
Method Western blot
Cell Lines A549 cells
Concentrations 0-10 μM
Incubation Time 24 h
Results PP242 treatment resulted in a reduction of AKT-473 phosphorylation in A549 cells.

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Rating
Source Torkinib (PP242) purchased from Selleck
Method Western Blot
Cell Lines HeLa cells
Concentrations 0/5/50/500/5000 nM
Incubation Time 24 h
Results

Product Citations (11)

Tech Support & FAQs

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