|Solubility (25°C) *||In vitro||DMSO||69 mg/mL warmed (197.83 mM)|
|In vivo||30% PEG400+0.5% Tween80+5% propylene glycol||5 mg/mL|
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
|Description||AZD1480 is a novel ATP-competitive JAK2 inhibitor with IC50 of 0.26 nM in a cell-free assay, selectivity against JAK3 and Tyk2, and to a smaller extent against JAK1. Phase 1.|
|In vitro||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. |
|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. |
|kinase assays||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 lines||Renca or 786-O cells, mouse endothelial cells and splenic CD11b+/c-myeloid cells, HUVECs|
|Incubation Time||48 or 24 hours|
|Method||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.|
|Animal Models||Female BALB/c and athymic nude (NCR - nu/nu) mice (7–8 weeks old)|
|Formulation||AZD1480 is suspended in water supplemented with 0.5% hypromellose and 0.1% Tween 80.|
|Dosages||Once a day at the dose of 50 mg/kg or twice daily at 30 mg/kg|
Data from [Data independently produced by , , Nat Cell Biol, 2015, 17(1): 57-67]
bDNA analysis showing that the JAK1/2 inhibitors CYT387, AZD1480 and Baricitinib positively regulate UCP1 expression in PSC-WA. Values are mean ± s.d. of n = three biological replicates and differences from DMSO are significant for * P < 0.005. P values were calculated using the two-tailed paired Student's t-test.
Data from [Data independently produced by , , Int J Obes, 2018, 42(2):252-259]
Adipocytes were pre-infected with pAd-Foxc2 or si-Foxc2, and incubated with AZD1480 or not. Figures show protein levels of leptin, IL-6 and TNFα in adipocytes.
White-to-brown metabolic conversion of human adipocytes by JAK inhibition. [Moisan A, et al. Nat Cell Biol, 2015, 17(1):57-67]PubMed: 25487280
Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations [Traer E, et al Blood, 2014, 123(10):1516-24]PubMed: 24408322
Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. [Deshpande A, et al. Leukemia, 2012, 26(4):708-15]PubMed: 21926964
Tyrosine receptor kinase B is a drug target in astrocytomas [Ni J, et al. Neuro Oncol, 2016, 10.1093/neuonc/now139]PubMed: 27402815
Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation. [ Cell Rep, 2015, 10.1016/j.celrep.2015.04.049]PubMed: 26027934
Tumoricidal effects of the JAK inhibitor Ruxolitinib (INC424) on hepatocellular carcinoma in vitro. [Wilson GS Cancer Lett, 2013, 341(2):224-30]PubMed: 23941832
TSLP signaling network revealed by SILAC-based phosphoproteomics. [Zhong J Mol Cell Proteomics, 2012, 11(6):M112.017764]PubMed: 22345495
Foxc2 coordinates inflammation and browning of white adipose by leptin-STAT3-PRDM16 signal in mice. [Karakas , et al. Int J Obes , 2018, 42(2):252-259]PubMed: 28925407
Dehydrocrenatidine is a Novel JAK Inhibitor. [Zhang J, et al. Mol Pharmacol, 2015, 87(4):572-81]
Growth hormone potentiates 17β-estradiol-dependent breast cancer cell proliferation independently of IGF-I receptor signaling. [Felice DL, et al. Endocrinology, 2013, 154(9):3219-27]PubMed: 23782942
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