AZD1480

JAK2 inhibitor,ATP-competitive and novel CAS# 935666-88-9

AZD1480

2D Structure

Catalog No. BCC2191----Order now to get a substantial discount!

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AZD1480

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Chemical Properties of AZD1480

Cas No. 935666-88-9 SDF Download SDF
PubChem ID 16659841 Appearance Powder
Formula C14H14ClFN8 M.Wt 348.77
Type of Compound N/A Storage Desiccate at -20°C
Synonyms AZD1480; AZD 1480
Solubility DMSO : 50 mg/mL (143.36 mM; Need ultrasonic)
Chemical Name 5-chloro-2-N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-4-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
SMILES CC1=CC(=NN1)NC2=NC(=NC=C2Cl)NC(C)C3=NC=C(C=N3)F
Standard InChIKey PDOQBOJDRPLBQU-QMMMGPOBSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AZD1480

DescriptionPotent and selective JAK2 inhibitor (IC50 < 3 nM). Exhibits >50-fold selectivity for JAK2 over JAK3. Exhibits antitumor effects and inhibits formation of lung metastases in a mouse renal cancer model. Also inhibits STAT3 signaling, tumor angiogenesis and myeloid cell migration in vivo.

AZD1480 Dilution Calculator

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AZD1480 Molarity Calculator

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Preparing Stock Solutions of AZD1480

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.8672 mL 14.3361 mL 28.6722 mL 57.3444 mL 71.6805 mL
5 mM 0.5734 mL 2.8672 mL 5.7344 mL 11.4689 mL 14.3361 mL
10 mM 0.2867 mL 1.4336 mL 2.8672 mL 5.7344 mL 7.168 mL
50 mM 0.0573 mL 0.2867 mL 0.5734 mL 1.1469 mL 1.4336 mL
100 mM 0.0287 mL 0.1434 mL 0.2867 mL 0.5734 mL 0.7168 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AZD1480

AZD1480 is a novel small-molecule JAK inhibitor. It is able to block cell proliferation and induce apoptosis of myeloma cell lines. It can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells. AZD1480 has broad efficacy on a wider variety of myeloma cells, such as RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9, as well as primary myeloma cells. 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 also demonstrates important Jak2 selectivity over Jak3, in particular at high ATP concentrations and marginal selectivity over Jak1 at Km ATP.

Reference

A Scuto, P Krejci, L Popplewell, J Wu, Y Wang, M Kujawski, C Kowolik, H Xin, L Chen, Y Wang, L Kretzner, H Yu, W R Wilcox, Y Yen, S Forman and R Jove. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia. 2011 March ; 25(3): 538–550

Michael Hedvat, Dennis Huszar, Andreas Herrmann, Joseph M. Gozgit, Anne Schroeder, Adam Sheehy, Ralf Buettner, David Proia, Claudia M. Kowolik, Hong Xin, Brian Armstrong, Geraldine Bebernitz, Shaobu Weng, Lin Wang, Minwei Ye, Kristen McEachern, Huawei Chen, Deborah Morosini, Kirsten Bell, Marat Alimzhanov, Stephanos Ioannidis, Patricia McCoon, Zhu A. Cao, Hua Yu, Richard Jove, Michael Zinda. The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors. Cancer Cell. 2009; 16 (6): 487–497

Hong Xin, Andreas Herrmann, Karen Reckamp, Wang Zhang, Sumanta Pal, Michael Hedvat, Chunyan Zhang, Wei Liang, Anna Scuto, Shaobu Weng, Deborah Morosini, Zhu A. Cao, Michael Zinda, Robert Figlin, Dennis Huszar, Richard Jove, Hua Yu. Antiangiogenic and Antimetastatic Activity of JAK Inhibitor AZD1480. Cancer Research. 2011;71: 6601-6610

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References on AZD1480

A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis.[Pubmed:25530567]

Leuk Res. 2015 Feb;39(2):157-63.

The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.

The JAK2 inhibitor AZD1480 inhibits hepatitis A virus replication in Huh7 cells.[Pubmed:25704089]

Biochem Biophys Res Commun. 2015 Mar 20;458(4):908-12.

The JAK2 inhibitor AZD1480 has been reported to inhibit La protein expression. We previously demonstrated that the inhibition of La expression could inhibit hepatitis A virus (HAV) internal ribosomal entry-site (IRES)-mediated translation and HAV replication in vitro. In this study, we analyzed the effects of AZD1480 on HAV IRES-mediated translation and replication. HAV IRES-mediated translation in COS7-HAV-IRES cells was inhibited by 0.1-1 muM AZD1480, a dosage that did not affect cell viability. Results showed a significant reduction in intracellular HAV HA11-1299 genotype IIIA RNA levels in Huh7 cells treated with AZD1480. Furthermore, AZD1480 inhibited the expression of phosphorylated-(Tyr-705)-signal transducer and activator of transcription 3 (STAT3) and La in Huh7 cells. Therefore, we propose that AZD1480 can inhibit HAV IRES activity and HAV replication through the inhibition of the La protein.

Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia.[Pubmed:25504635]

Mol Cancer Ther. 2015 Feb;14(2):364-74.

Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAK). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immunodeficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The antileukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL.

Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.[Pubmed:26494904]

Hum Mol Genet. 2016 Jan 1;25(1):9-23.

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated.

Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)p yrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway.[Pubmed:21138246]

J Med Chem. 2011 Jan 13;54(1):262-76.

The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.

Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.[Pubmed:21920898]

Cancer Res. 2011 Nov 1;71(21):6601-10.

STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed antiangiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these antiangiogenic effects, showing the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells.

Description

AZD-1480 is an ATP-competitive inhibitor of JAK1 and JAK2 with IC50s of 1.3 nM and <0.4 nM, respectively.

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