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    PP121
    PP121

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0200
    CAS #: 1092788-83-4Purity ≥98%

    Description: PP-121 is a novel, potent and selective multi-targeted RTK (receptor tyrosine kinases) inhibitor with potential antitumor activity. It inhibits several kinases such as  DNA-PK, PDGFR, Hck, mTOR, VEGFR2, Src and Abl with IC50 of 60 nM, 2 nM, 8 nM, 10 nM, 12 nM, 14 nM and 18 nM, respectively. It showed potent antiproliferative activity in vitro and high antitumor efficacy in vivo.

    References:Nat Chem Biol. 2008 Nov;4(11):691-9.

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    Molecular Weight (MW)

    319.36

    Formula

    C17H17N7 

    CAS No.

    1092788-83-4

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 64 mg/mL (200.4 mM)

    Water: <1 mg/mL

    Ethanol: 2 mg/mL (6.26 mM)

    Other info

    Chemical Name: 1-Cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

    InChi Key: NVRXTLZYXZNATH-UHFFFAOYSA-N

    InChi Code: InChI=1S/C17H17N7/c18-15-13-14(11-7-10-5-6-19-16(10)20-8-11)23-24(12-3-1-2-4-12)17(13)22-9-21-15/h5-9,12H,1-4H2,(H,19,20)(H2,18,21,22)

    SMILES Code: NC1=C2C(N(C3CCCC3)N=C2C4=CN=C(NC=C5)C5=C4)=NC=N1

    Synonyms

    PP121; PP-121; PP 121


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    In Vitro

    Kinase Assay: Purified kinase domains are incubated with PP-121 at 2- or 4-fold dilutions over a concentration range of 1nM-50 µM or with vehicle (0.1% DMSO) in the presence of 10 µM ATP, 2.5 µCi of γ-32P-ATP and substrate. Reactions are terminated by spotting onto nitrocellulose or phosphocellulose membranes, depending on the substrate; this membrane is then washed 5–6 times to remove unbound radioactivity and dried. Transferred radioactivity is quantitated by phosphorimaging and IC50 values are calculated by fitting the data to a sigmoidal doseresponse using Prism software.

     

    Cell Assay: For western blot analysis, cells (U87, LN229, NIH3T3, HUVECs, BaF3 and TT thyroid carcinoma cells) are grown in 12-well plates and treated with PP-121 at the indicated concentrations or vehicle (0.1% DMSO). Treated cells are lysed, lysates are resolved by SDS-PAGE, transferred to nitrocellulose and blotted. For cell proliferation assays,cells are grown in 96-well plates are treated with PP-121 at 4-fold dilutions (10 µM - 0.040 μM) or vehicle (0.1% DMSO). After 72 hours cells are exposed to Resazurin sodium salt (22 µM) and fluorescence is quantified. IC50 values are calculated using Prism software. For proliferation assays involving single cell counting, non-adherent cells are plated at low density (3–5% confluence) and treated with PP-121 (2.5 µM) or vehicle (0.1% DMSO). Cells are diluted into trypan blue daily and viable cells counted using a hemocytometer. For apoptosis and cell cycle analysis, cells are treated with the indicated concentration of PP-121 or vehicle (0.1% DMSO) for 24–72 hours. Cells are either stained live with AnnexinV-FITC or fixed with ethanol and stained with propidium iodide. Cell populations are separated using a FacsCalibur flow cytometer; data is collected using CellQuest Pro software and analyzed with either ModFit or FlowJo Software.

    PP-121 selectivity interacts within a hydrophobic pocket that is conserved between both tyrosine kinases and PI3Ks, not serine-threonine kinases. PP-121 makes a hydrogen bond to Glu310 in Src, effectively substituting for the structural role of the catalytic lysine and resulting in the ordering of helix C and stabilization of an active conformation. PP-121 also inhibits other PI3Ks including p110α and DNA-PK with IC50 of 52 nM and 60 nM, respectively. PP-121 potently and dose-dependently blocks the phosphorylation of Akt, p70S6K and S6 in two glioblastoma cell lines, U87 and LN229. PP-121 potently inhibits the proliferation of a subset of the tumor cell lines by direct inhibition of PI3Ks and mTOR. PP-121 induces a G0/G1 arrest in LN220, U87 and Seg1 cells. PP-121 also blocks tyrosine phosphorylation induced by v-Src in NIH3T3 cells transformed with v-Src(Thr338). PP-121 could restore actin stress fiber staining in NIH3T3 cells transformed with v-Src(Thr338). PP-121 at a low concentration of 40 nM inhibits Ret autophosphorylation in TT thyroid carcinoma cells that express the C634W oncogenic Ret mutant35. PP-121 inhibits cell proliferation with IC50 of 50 nM in TT thyroid carcinoma cells. PP-121 inhibits cell proliferating stimulated only with VEGF with IC50 of 41 nM in human umbilical vein endothelial cells (HUVECs). PP-121 directly inhibits Bcr-Abl induced tyrosine phosphorylation, resulting in drug-induced apoptosis in K562 cells and a combination of apoptosis and cell cycle arrest in Bcr-Abl expressing BaF3 cells.

    In Vivo

    Oral administration of PP121 remarkably inhibits Eca-109 xenograft growth. Mice body weights are not significantly affected by PP121 or the vehicle treatment. PP121 oral administration dramatically inhibits activations of Akt-mTOR and NFkB in xenograft tumors. p-Akt Ser 473 and p-IKKa/b are both inhibited by PP121 administration.

    Animal model

    Mice: Eca-109 cells are injected into the axillary regions of nude mice (5×106 cells/mouse). When the tumor volumes reach around 200 mm3, the mice are randomly separated to three groups: Untreated control, PP121 (30 mg/kg) and vehicle (10% 1-methyl-2-pyrrolidinone and 90% PEG 300) group. Tumor volumes and the mice body weights are measured every 10 d.

    Formulation & Dosage

    30 mg/kg; dissolved in 10% 1-methyl-2-pyrrolidinone and 90% PEG 300

    References

    Nat Chem Biol. 2008 Nov;4(11):691-9; Peng Y, et al. The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121. Biochem Biophys Res Commun. 2015 Sep 11;465(1):137-44.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

     
    PP121
    PP121 directly inhibits p110α/mTOR. Nat Chem Biol. 2008 Nov;4(11):691-9
     
    PP121
    PP121 directly inhibits Src


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