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    Pictilisib (GDC0941, RG7321, GNE0941))
    Pictilisib (GDC0941, RG7321, GNE0941))

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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 #: V0102
    CAS #: 957054-30-7Purity ≥98%

    Description: Pictilisib (also called GDC-0941, Pictrelisib, RG-7321 and GNE-0941) is a potent and orally bioavailable inhibitor of PI3Kα/δ (class I phosphatidylinositol 3 kinase) with IC50 of 3 nM in cell-free assays. It has potential anticancer activity and showed modest selectivity against p110β (11-fold) and p110γ (25-fold). Activation of PI3K/Akt signaling pathway is frequently associated with tumorigenesis. Deregulation of this pathway occurs frequently with a variety of cancers and may contribute to the resistance to many anticancer agents. Developing novel small molecules that specifically block the PI3K/Akt pathway may inhibit tumor growth. GDC-0941 is designed to bind the ATP-binding pocket of PI3K and to prevent formation of phosphatidylinositol-3, 4, 5-triphosphate (PIP3), a second messenger that transmits PI3K downstream signals. It binds to PI3K in an ATP-competitive manner.

    References: Oncogene. 2008 Sep 18;27(41):5497-510; J Med Chem. 2008 Sep 25;51(18):5522-32.

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    Molecular Weight (MW)

    513.64

    Formula

    C23H27N7O3S2

    CAS No.

    957054-30-7

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 44 mg/mL (85.66 mM)

    Water:<1 mg/mL (slightly soluble or insoluble)

    Ethanol: <1 mg/mL (slightly soluble or insoluble)

    Solubility (In vivo)

    2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5 mg/mL

    Chemical Name

    4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine

    Synonyms

    Pictrelisib; Pictilisib; RG7321; RG-7321; RG 7321; GDC-0941; GDC 0941; GDC0941; GNE0941; GNE-0941; GNE 0941; 

    SMILES

    O=S(N1CCN(CC2=CC3=NC(C4=CC=CC5=C4C=NN5)=NC(N6CCOCC6)=C3S2)CC1)(C)=O


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    In Vitro

    Kinase Assay: Scintillation proximity assay; Recombinant human PI3Kα, PI3Kβ, and PI3Kδ are coexpressed in a Sf9 baculovirus system with the p85α regulatory subunit and purified as GST-fusion proteins using affinity chromatography on glutathione-sepharose. Recombinant human PI3Kγ is expressed as monomeric GST-fusions and purified similarly. GDC-0941 is dissolved in DMSO and added to 20 mM Tris-HCl (pH 7.5) containing 200 μg yttrium silicate (Ysi) polylysine SPA beads, 4 mM MgCl2, 1 mM dithiothreitol (DTT), 1 μM ATP, 0.125 μCi [γ-33P]-ATP, and 4% (v/v) DMSO in a total volume of 50 μL. The recombinant GST-fusion of PI3Kα (5 ng), PI3Kβ (5 ng), PI3Kδ (5 ng), or PI3Kγ (5 ng) is added to the assay mixture to initiate the kinase reaction. After incubation for 1 hour at room temperature, the kinase reaction is terminated with 150 μL PBS. The mixture is then centrifuged for 2 minutes at 2000 rpm and read using a Wallac Microbeta counter. The reported IC50 values are calculated using a sigmoidal, dose-response curve fit in MDL Assay Explorer.

     

    Cell Assay: SKBR-3, BT474-M1, AU-565, HCC-1419, ZR75-30, KPL-4, JIMT-1, BT474-EEI, HCC-1954, MCF-7, CALU-3, SKOV-3, and MKN-7 cells; ~10 μM concentration; 48 and 72 hours; Cells are exposed to various concentrations of GDC-0941 for 48, and 72 hours. Proliferation/viability of cells is detected by using the CellTiter-Glo Luminescent Cell Viability Assay. The pAkt (Ser473), cleaved caspase-3, and cleaved PARP are analyzed by western blot. The Caspase-Glo 3/7 assay and the Cell Death Detection ELISAplus assay are used to detect caspase 3/7 activity, and apoptosis, respectively.

    GDC-0941 is equipotent against PI3Kα and PI3Kδ as well as PI3Kα mutants E545-K and H1047-R, displaying modest levels of selectivity against PI3Kβ (10-fold) and PI3Kγ (25-fold), and greater levels of selectivity against members of PI3K class II, III, and IV, including C2β, Vps34, DNA-PK, and mTOR. GDC-0941 potently inhibits the phosphorylation of Akt in U87MG, PC3, and MDA-MB-361 cells with IC50 of 46 nM, 37 nM, and 28 nM, respectively. GDC-0941 inhibits the proliferation of U87MG, A2780, PC3, and MDA-MB-361 cells with IC50 of 0.95 μM, 0.14 μM, 0.28 μM, and 0.72 μM, respectively. GDC-0941 treatment potently inhibits the proliferation of both trastuzumab-sensitive and -insensitive HER2-amplified cells with IC50 of 149-944 nM. GDC-0941 inhibits proliferation of HER2-amplified cells that harbor PIK3CA mutations with IC50 of<500 nM, and effectively inhibits both proliferation and viability of HER2-amplified breast cancer cells that are resistant to trastuzumab due to PTEN loss. GDC-0941 significantly inhibits the growth of HCT116, DLD1 and HT29 cells with GI50 of 1081 nM, 1070 nM and 157 nM, respectively. GDC-0941 inhibits tumor cell proliferation, induces apoptosis and suppresses centroblast population

    In Vivo

    Administration of GDC-0941 at 75 mg/kg/day displays significant inhibitory effect against established human U87MG glioblastoma xenografts in female NCr athymic mice, with tumor growth inhibition of 83%. Oral administration of GDC-0941 at 150 mg/kg/day inhibits the growth of HER2-amplified, trastuzumab-resistant MDA-MB-361.1 xenografts in mice, and significantly delays the tumor progression, in association with potent induced apoptosis in tumors. GDC-0941 (75 mg/kg/day) treatment for 2 weeks induces ~40% reduction in tumor volume of spontaneous B-cell follicular lymphomas developed in PTEN+/-LKB1+/hypo mice, accompanied by ablation of phosphorylation of Akt, S6K and SGK (serum and glucocorticoid protein kinase) protein kinases.

    Animal model

    NCR nude mice implanted with MDA-MB-361.1 cells, and SCID, C.B-17/IcrHsd-Prkdcscid mice implanted subcutaneously with BT474-M1 cells.

    Formulation & Dosage

    10% DMSO, 5% Tween 20, 85% water; 150 mg/kg; oral

    References

    [1] Folkes AJ, et al. J Med Chem, 2008, 51(18), 5522-5532.[2] Junttila TT, et al. Cancer Cell, 2009, 15(5), 429-440.


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

    Pictilisib (GDC-0941)

    Pictilisib (GDC-0941)
    Pictilisib (GDC-0941)


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