AZD1480 is a potent JAK2 inhibitor with an IC50 of 0.26 nM. AZD1480 inhibits constitutive and stimulus-induced phosphorylation of JAK2 and STAT-3 in vitro, downstream gene expression, and inhibits cell proliferation. AZD1480 suppresses STAT-3 activation in the glioma-initiating cell population in glioblastoma (GBM) tumors. In vivo, AZD1480 inhibits the growth of subcutaneous tumors and increases survival of mice bearing intracranial GBM tumors by inhibiting STAT-3 activity. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo, and leads to a decrease in cell proliferation and induction of apoptosis.
|Cell lines||Renca or 786-O cells|
|Preparation method||Cell viability assay.
Renca or 786-O cells suspended in DMEM medium with 5% FBS were seeded in 96-well plates (5,000 per well) to allow adhesion and then treated with DMSO or AZD1480 for 48 h. Cell viability was determined by MTS assay (Promega, Madison, WI) according to instructions. Absorbance at 490 nm was measured with Mikrotek Laborsysteme (Overath, Germany). Mouse ECs and splenic CD11b+/c− myeloid cells enriched from tumor bearing mice were cultured in 5% FBS 1640 RPMI medium. HUVECs were cultured on collagen 1-coated plates in complete medium (Clonetics). All cells are treated with DMSO and AZD1480 at various doses for 24 h. Cell viability was determined by counting cell number manually. All the experiments were repeated 3 times.
|Concentrations||0, 0.1, 0.5, 1.0, 2.5, and 5 μM|
|Incubation time||48 h|
|Animal models||Female BALB/c and athymic nude (NCR-nu/nu) mice (7-8 weeks old)|
|Formulation||water supplemented with 0.5% Hypromellose and 0.1% Tween 80|
|Dosages||50 mg/kg once a day or 30 mg/kg twice daily for 21 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 65 mg/mL|
The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma.
Derenzini E, et al. Blood Cancer J. 2011 Dec;1(12):e46. PMID: 22829094.
Therapeutic potential of AZD1480 for the treatment of human glioblastoma.
McFarland BC, et al. Mol Cancer Ther. 2011 Dec;10(12):2384-93. PMID: 22027691.
Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.
Xin H, et al. Cancer Res. 2011 Nov 1;71(21):6601-10. PMID: 21920898.
The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival.
Scuto A, et al. Leukemia. 2011 Mar;25(3):538-50. PMID: 21164517.
The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors.
Hedvat M, et al. Cancer Cell. 2009 Dec 8;16(6):487-97. PMID: 19962667.
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Oclacitinib is a novel inhibitor of JAK family members with IC50 ranging from 10 to 99 nM and JAK1-dependent cytokines with IC50 ranging from 36 to 249 nM, which did not inhibit a panel of 38 non-JAK kinases.
Baricitinib phosphate(INCB 028050; LY 3009104) is a selective JAK1 and JAK2 inhibitor with IC50 of 5.9 nM and 5.7 nM, ~70 and ~10-fold selective versus JAK3 and Tyk2, no inhibition to c-Met and Chk2.
Janex-1 is a cell-permeable, reversible, potent, ATP-competitive, and specific inhibitor of JAK3 (IC50 = 78 μM); has no effect on JAK1, JAK2, or Zap/Syk or SRC tyrosine kinases.
Decernotinib is a potent and selective Janus kinase 3 (JAK3) inhibitor with Ki of 2.5 nM; IC50 is 50-170 nM in cellular assays.
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