Torkinib (PP242)

Catalog No.S2218 Batch:S221806

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Technical Data

Formula

C16H16N6O
Molecular Weight 308.34 CAS No. 1092351-67-1
Solubility (25°C)* In vitro DMSO 61 mg/mL (197.83 mM)
Water Insoluble
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Torkinib (PP242) is a selective mTOR inhibitor with IC50 of 8 nM in cell-free assays; targets both mTOR complexes with >10- and 100-fold selectivity for mTOR than PI3Kδ or PI3Kα/β/γ, respectively. Torkinib (PP242) induces mitophagy and apoptosis.
Targets
mTOR [1]
(Cell-free assay)		 p110δ [1]
(Cell-free assay)		 DNA-PK [1]
(Cell-free assay)		 PDGFR [1]
(Cell-free assay)
8 nM 0.10 μM 0.41 μM 0.41 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 (from 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

  • Dosages

    ~60 mg/kg/day

  • Administration

    Oral gavage

Customer Product Validation

Data from [Data independently produced by Mol Cancer Ther, 2014, 13(1), 37-48]

Data from [Data independently produced by Mol Cell Biol, 2014, 34(13), 2517-32]

Data from [Data independently produced by Cancer Res, 2013, 73(11), 3402-11]

Data from [Data independently produced by Autophagy, 2012, 8(6), 903-14]

Selleck's Torkinib (PP242) has been cited by 100 publications

Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis [ Cell Death Dis, 2024, 15(1):48] PubMed: 38218922
TRIM44 promotes autophagy through SQSTM1 oligomerization in the response to oxidative stress induced by Arsenic Trioxide in cancer cells [ Res Sq, 2024, rs.3.rs-3951960] PubMed: 38464079
Spatial patterns of the cap-binding complex eIF4F in human melanoma cells [ Comput Struct Biotechnol J, 2023, 21:1157-1168] PubMed: 36789267
Claspin is Required for Growth Recovery from Serum Starvation through Regulating the PI3K-PDK1-mTOR Pathway in Mammalian Cells [ Mol Cell Biol, 2023, 43(1):1-21] PubMed: 36720467
Three generations of mTOR kinase inhibitors in the activation of the apoptosis process in melanoma cells [ J Cell Commun Signal, 2023, 17(3):975-989] PubMed: 37097377
Activation of Lysosomal Function Ameliorates Amyloid-β-Induced Tight Junction Disruption in the Retinal Pigment Epithelium [ Mol Cells, 2023, 46(11):675-687] PubMed: 37968982
mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance [ Oncol Res, 2023, 31(4):495-503] PubMed: 37415733
Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence [ bioRxiv, 2023, 2023.02.14.528513] PubMed: 36824760
Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function [ Immunity, 2022, 55(1):159-173.e9] PubMed: 34982959
S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions [ Nat Commun, 2022, 13(1):1548] PubMed: 35318320

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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