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    AZD1480
    AZD1480

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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 #: V0316
    CAS #: 935666-88-9Purity ≥98%

    Description: AZD1480 is a novel, potent, orally bioavailable, and ATP-competitive JAK2 (Janus-associated kinase) inhibitor with IC50 of 0.26 nM in a cell-free assay. It has potential antineoplastic activity. It inhibits JAK2 activation which leads to the inhibition of the JAK/STAT signaling including activation of STAT3. This may lead to induction of tumor cell apoptosis and a decrease in cellular proliferation. JAK2, often upregulated or mutated in a variety of cancer cells, mediates STAT3 activation and plays a key role in tumor cell proliferation and survival.

    References: Blood Cancer J. 2011 Dec; 1(12): e46; Mol Cancer Ther. 2011 Dec;10(12):2384-93; Cancer Res. 2011 Nov 1;71(21):6601-10.  

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    AZD1480

    Name: AZD-1480
    CAS#: 935666-88-9
    Chemical Formula: C14H14ClFN8
    Exact Mass: 348.1014
    Molecular Weight: 348.76596
    Elemental Analysis: C, 48.21; H, 4.05; Cl, 10.17; F, 5.45; N, 32.13
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Technical InformationSynonym: AZD-1480; AZD1480; AZD 1480
    Chemical Name: (S)-5-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
    InChi Key: PDOQBOJDRPLBQU-QMMMGPOBSA-N
    InChi Code: InChI=1S/C14H14ClFN8/c1-7-3-11(24-23-7)21-13-10(15)6-19-14(22-13)20-8(2)12-17-4-9(16)5-18-12/h3-6,8H,1-2H3,(H3,19,20,21,22,23,24)/t8-/m0/s1
    SMILES Code: CC1=CC(NC2=NC(N[[email protected]](C3=NC=C(F)C=N3)C)=NC=C2Cl)=NN1


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    In Vitro

    In vitro activity: 5μM AZD1480 induces G2/M arrest and cell death by inhibiting Aurora kinases. AZD1480 is a potent JAK2 inhibitor that can suppress growth, survival, as well as FGFR3 and STAT3 signaling and downstream targets including Cyclin D2 in human multiple myeloma cells. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines.AZD1480 effectively blocks constitutive and stimulus-induced JAK1, JAK2, and STAT-3 phosphorylation in both human and murine glioma cells, and leads to a decrease in cell proliferation and induction of apoptosis. AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase, and that it is capable of inhibiting STAT3 phosphorylation and tumor growth in a STAT3-dependent manner. AZD1480 inhibits tumor angiogenesis and metastasis in part by affecting the tumor microenvironment.

     

    Kinase Assay: Inhibition studies of AZD1480 are performed using recombinant Jak1, Jak2, or Jak3 under buffer conditions of 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween-20, 50 mM/ml BSA, and 10 mM MgCl2. Jak3 enzyme is expressed as N-terminal GST fusion in insect cells and purified by glutathione-affinity and size-exclusion chromatographies. Enzymes are assayed in the presence of AZD1480 (10 point dose response, in triplicate, from 8.3 μM to 0.3 nM in half-log dilution steps) using 1.5 μM peptide substrate (Jak1: FITC-C6-KKHTDDGYMPMSPGVA-NH2, Jak2 and Jak3: FAM-SRCtide) and screened under their respective ATP Km (Jak1: 55 μM, Jak2: 15 μM, Jak3: 3 μM) and approximated physiological ATP concentration of 5 mM. Phosphorylated and unphosphorylated peptides are separated and quantified by a Caliper LC3000 system for calculating percent inhibition.

     

    Cell Assay: Renca or 786-O cells are suspended in DMEM medium with 5% FBS , and seeded in 96-well plates (5×103 per well) to allow adhesion and then treated with DMSO or AZD1480 for 48 hours. Cell viability is determined by MTS assay. Absorbance at 490 nm is measured with Mikrotek Laborsysteme. Mouse endothelial cells and splenic CD11b+/c- myeloid cells are enriched from tumor-bearing mice,and cultured in 5% FBS RPMI-1640 medium. HUVECs are cultured on collagen 1–coated plates in complete medium. All cells are treated with DMSO and AZD1480 at various doses for 24 hours. Cell viability is determined by counting cell number manually. All the experiments are repeated 3 times.

    In Vivo

    AZD1480 inhibits the STAT3 phosphorylation in an xenograft model of human solid tumors and multiple myeloma. In vivo, AZD1480 inhibits the growth of subcutaneous tumors and increases survival of mice bearing intracranial glioblastoma (GBM) tumors by inhibiting STAT-3 activity, indicating that pharmacologic inhibition of the JAK/STAT-3 pathway by AZD1480 should be considered for study in the treatment of patients with GBM tumors. AZD1480 blocks lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduces angiogenesis and metastasis in a human xenograft tumor model. The Jak2 inhibitor, AZD1480, suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity.

    Animal model

    SCID/Beige mice injected with TC32 or Rh18 cells

    Formulation & Dosage

    Formulated in water supplemented with 0.5% hypromellose and 0.1% Tween 80.; 30 mg/kg; Oral gavage

    References

    Blood Cancer J. 2011 Dec; 1(12): e46; Mol Cancer Ther. 2011 Dec;10(12):2384-93; Cancer Res. 2011 Nov 1;71(21):6601-10; Cancer Cell. 2009 Dec 8;16(6):487-97.  


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

    AZD1480

    AZD1480 inhibits spontaneous lung metastasis of mouse syngeneic tumors. Cancer Res.2011 Nov 1;71(21):6601-10.

    AZD1480

    AZD1480 inhibits experimental lung metastasis of mouse syngeneic tumors. Cancer Res. 2011 Nov 1;71(21):6601-10.

    AZD1480

    AZD1480 inhibits angiogenesis and metastasis in 786-O xenografts and over-expression of constitutively active STAT3 rescues 786-O tumor from angiogenic inhibition. Cancer Res. 2011 Nov 1;71(21):6601-10. 

     

    AZD1480

    Baseline JAK/STAT pathway activation status and effects of AZD1480 in HL cell lines.  2011 Dec;1(12):e46.

     

    AZD1480

    AZD1480 induces paradoxical hyperphosphorylation of JAK2, TYK2 and MAP Kinases (ERK, p38) in HL cells.  2011 Dec;1(12):e46.

     

    AZD1480

    AZD1480 induces G2/M cell cycle arrest by inhibition of Aurora A in HL cell lines.  2011 Dec;1(12):e46.



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