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    SNX-2112 (PF-04928473)
    SNX-2112 (PF-04928473)

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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 #: V0888
    CAS #: 908112-43-6Purity ≥98%

    Description: SNX-2112 (SNX2112; SNX 2112; PF-04928473; PF04928473) is a novel and potent HSP90 (Heat Shock Protein 90) with potential antitumor activity and was in phase 1 clinical trials. It selectively inhibits HSP90α and HSP90β with Ka values of 30 nM and 30 nM. It exhibits excellent in vivo antitumor efficacy in in a xenograft murine model.

    References: Clin Cancer Res. 2008 Jan 1;14(1):240-8; Blood. 2009 Jan 22;113(4):846-55.

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    Molecular Weight (MW)464.48
    FormulaC23H27F3N4O3
    CAS No.908112-43-6
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 93 mg/mL (200.2 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)0.5% CMC+0.25% Tween 80: 30mg/mL  
    Other info

    Synonym:  PF 04928473; SNX2112; SNX-2112; PF-04928473; PF04928473; SNX 2112;

    Chemical Name: 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-(((1r,4r)-4-hydroxycyclohexyl)amino)benzamide

    InChi Key: ZFVRYNYOPQZKDG-MQMHXKEQSA-N

    InChi Code: InChI=1S/C23H27F3N4O3/c1-22(2)10-17-19(18(32)11-22)20(23(24,25)26)29-30(17)13-5-8-15(21(27)33)16(9-13)28-12-3-6-14(31)7-4-12/h5,8-9,12,14,28,31H,3-4,6-7,10-11H2,1-2H3,(H2,27,33)/t12-,14-

    SMILES Code: O=C(N)C1=CC=C(N2N=C(C(F)(F)F)C3=C2CC(C)(C)CC3=O)C=C1N[[email protected]]4CC[[email protected]](O)CC4


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    In Vitro

    In vitro activity: Treatment of BT-474 cells with 1 μM SNX-2112 results in down-regulation of HER2 expression within 3 to 6 hours of drug exposure with near-complete loss of HER2 expression by 10 hours. Treatment with SNX-2112 also results in a decline in total Akt expression. SNX-2112 inhibits cell proliferation with IC50 values ranging from 10 to 50 nM, in BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 and H1650 cancer cells. And these antiproliferative effects are associated with hypophosphorylation of Rb, arrest of G1 and modest levels of apotosis. SNX-2112 competitively binds to the N-terminal adenosine triphosphate binding site of Hsp90. SNX-2112 induces apoptosis via caspase-8, -9, -3, and poly (ADPribose) polymerase cleavage. SNX-2112 inhibits cytokine-inducedAkt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Cell lines (eight cell lines from osteosarcoma, neuroblastoma, hepatoblastoma, and ymphoma) studied demonstrates sensitivity to SNX-2112 with IC50 values ranging from 10-100 nM. A higher dose (70 nM) exhibits a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of Akt1 and C-Raf are markedly reduced over time along with an increase in PARP cleavage. A recent research indicates NX-2112 induces autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and utophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent.


    Kinase Assay: For the protein affinity-displacement assay, a purine-based affinity resin is generated by incubating ATP-linked Sepharose with Jurkat cell lysate (flash frozen and homogenized in saline) at 4 °C. This is then incubated with SNX-2112 for 90 minutes. Proteins eluted by drug are then resolved by SDS-PAGE, visualized with silver staining, and excised from the gel for MS-based identification. Briefly, after destaining and trypsin digestion, peptides are extracted with μC18 ZipTips and then eluted and spotted directly to a conventional stainless steel matrix-assisted laser desorption/ionization target with a saturated solution of α-cyano-4- hydroxycinnamic acid in 50% acetonitrile, 0.15% formic acid. Mass spectra are then acquired using a MALDI-TOF/TOF 4700 Proteomics Analyzer. MS spectra are acquired (1,000 shots per spectrum), and the three peaks from each with the greatest signal-to-noise ratio are automatically submitted for tandem MS analysis (3000 shots per spectrum). The collision energy is 1keV. Air is used as the collision gas. Protein identification is done from the MS and tandem MS data using GPS Explorer software with the integrated Mascot database search engine.


    Cell Assay:  Cell viability is determined by seeding 2-5 × 103 cells (BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 and H1650 cancer cells) per well in 96- well plates and treating with SNX-2112 24 hours after plating in complete medium (200 μL). Each drug concentration is tested in eight wells. Cells are assayed using the Alamar blue viability test after a 96-h incubation. Flow cytometry is done using nuclei stained with ethidium bromide and isolated via the Nusse protocol

    In VivoSNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model and blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis.
    Animal model5 × 106 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice
    Formulation & DosageDissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C for in vivo study; 20 or 40 mg/kg; oral gavage
    References

    Clin Cancer Res. 2008 Jan 1;14(1):240-8; Blood. 2009 Jan 22;113(4):846-55.


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

    SNX-2112 (PF-04928473)


    SNX-2112 targets degradation of Hsp90 client protein. Blood. 2009 Jan 22;113(4):846-55.
     

    SNX-2112 (PF-04928473)

    SNX-2112 inhibits Akt and ERK pathway and overcomes the growth stimulatory effects of IL-6, IGF-1, and BMSCs on MM cell growth. Blood.2009 Jan 22;113(4):846-55.
     

    SNX-2112 (PF-04928473)

    SNX-5422 inhibits human MM cell growth and angiogenesis in vivo. Blood. 2009 Jan 22;113(4):846-55.


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