The signal transducer and activator of transcription (STAT) activation by cytokines is mediated through the Janus family kinases (Jak), which include four family members, Jak1, Jak2, Jak3, and Tyk2. JAK2 is a Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. JAK2 mediates essential signaling events in both innate and adaptive immunity. Following ligand-binding to cell surface receptors, JAK2 phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins.
AZD1480 is a potent ATP competitive inhibitor of JAK2 kinase, with an inhibition constant (Ki) of 0.26nM. The enzyme IC50 of AZD1480 against JAK2, JAK1 and JAK3 were <0.4nM, 1.3nM and 3.9nM, respectively, at Km ATP[3]. In TEL-JAK2 cells, AZD1480 concentration-dependently inhibited the phosphorylation of Stat5 ranging from 0.03μM to 1μM, with an IC50 of 46nM. Little or no inhibition of Stat5 phosphorylation was observed in the TEL-Jak3, TEL-Jak1, or TEL-Tyk2 cells at below 1μM AZD1480[3]. At concentrations ranging from 0.5μM to 3μM, AZD1480 blocked cell proliferation and induces apoptosis of myeloma cell lines[4]. In animal experiments, AZD1480 decreased tumor growth in Renca, Kms.11, TC32, Rh18 or patient derived Glioblastoma xenografts. In different experiments, AZD1480 was orally dosed 50mg/kg once a day or 30mg/kg, twice a day[5].
AZD-1480 细胞实验
Cell Line
Concentration
Treated Time
Description
References
PSCs
2 μM
48 h
AZD-1480 reduced IL6 expression induced by hypoxia, while rescuing hypoxia-mediated repression of αSMA
Cancer Res. 2023 May 15;83(10):1596-1610.
HNSCC cell lines
0.9 to 4 μM
72 h
AZD1480 inhibited HNSCC cell line proliferation and reduced pSTAT3 Tyr705 expression
Neoplasia. 2015 Mar;17(3):256-64.
RCAS high-grade cell line
1.0 μM
48 and 72 h
Measure cell growth, AZD1480 had no significant effect on cell proliferation
Clin Cancer Res. 2017 Jun 15;23(12):3109-3119.
U87 and U251 cells
0.5 and 1.0 μM
24, 48, and 72 h
Measure cell growth, AZD1480 had no significant effect on cell proliferation
Clin Cancer Res. 2017 Jun 15;23(12):3109-3119.
Mouse endothelial cells
0.5 μM
2 h
AZD1480 inhibited STAT3 phosphorylation induced by Renca tumor conditioned medium in mouse endothelial cells.
Cancer Res. 2011 Nov 1;71(21):6601-10.
DU145 cells
800 nM
72 h
AZD1480 suppressed IL-6-induced migration and heterotypic adhesion of DU145 cells, but did not significantly affect cell viability.
Mol Cancer Ther. 2014 May;13(5):1246-58.
CWR22Rv1 cells
800 nM
72 h
AZD1480 suppressed IL-6-induced migration and heterotypic adhesion of CWR22Rv1 cells.
Mol Cancer Ther. 2014 May;13(5):1246-58.
U251-MG
1 µM
30 min to 16 h
AZD1480 inhibited STAT-3 and JAK2 phosphorylation in U251-MG cells, leading to decreased cell proliferation and induction of apoptosis.
Mol Cancer Ther. 2011 Dec;10(12):2384-93.
U87-MG
1 µM
30 min to 16 h
AZD1480 inhibited STAT-3 and JAK2 phosphorylation in U87-MG cells, leading to decreased cell proliferation and induction of apoptosis.
Mol Cancer Ther. 2011 Dec;10(12):2384-93.
4C8
1 µM
30 min to 16 h
AZD1480 inhibited STAT-3 and JAK2 phosphorylation in 4C8 cells, leading to decreased cell proliferation and induction of apoptosis.
Mol Cancer Ther. 2011 Dec;10(12):2384-93.
GBM cells(STAT3 -high tumor cells)
0.1, 0.5, 1, 2 μM
5 days
To evaluate the effect of STAT3 inhibitors on GBM cell viability, results showed that STAT3-high cells were more sensitive to AZD1480, with significantly reduced viability.
Nat Commun. 2019 Aug 9;10(1):3601.
GBM cells(STAT3 -low tumor cells)
0.1, 0.5, 1, 2 μM
5 days
To evaluate the effect of STAT3 inhibitors on GBM cell viability, results showed that STAT3-low cells were not sensitive to AZD1480, with minimal changes in viability.
Nat Commun. 2019 Aug 9;10(1):3601.
UMSCC-1 cells
0.9 to 4 μM
72 h
To evaluate the effect of AZD-1480 on HNSCC cell proliferation, results showed that AZD-1480 inhibited cell proliferation and reduced pSTAT3 Tyr705 expression
Neoplasia. 2015 Mar;17(3):256-64.
HN5 cells
0.9 to 4 μM
72 h
To evaluate the effect of AZD-1480 on HNSCC cell proliferation, results showed that AZD-1480 inhibited cell proliferation and reduced pSTAT3 Tyr705 expression
Neoplasia. 2015 Mar;17(3):256-64.
Cal33 cells
0.9 to 4 μM
72 h
To evaluate the effect of AZD-1480 on HNSCC cell proliferation, results showed that AZD-1480 inhibited cell proliferation and reduced pSTAT3 Tyr705 expression
Neoplasia. 2015 Mar;17(3):256-64.
AZD-1480 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Patient-derived xenograft models
Oral
30 mg/kg
Twice daily for 13 to 15 days
AZD1480 significantly slowed tumor growth and reduced pSTAT3 Tyr705 expression
Neoplasia. 2015 Mar;17(3):256-64.
Mice
RCAS murine glioma model
Oral
60 mg/kg
Once daily, 5 days a week, for 3 weeks
AZD1480 blocks recruitment of CD11b+ cells to the tumor, reduces tumor burden, and prolongs survival
Clin Cancer Res. 2017 Jun 15;23(12):3109-3119.
Mice
Renca tumor model
Oral
50 mg/kg
Once daily for 21 days
AZD1480 significantly inhibited Renca tumor growth and reduced myeloid cell infiltration in the tumor microenvironment.
Cancer Res. 2011 Nov 1;71(21):6601-10.
Nude mice
Prostate cancer metastasis model
Oral
50 mg/kg
Daily for 8 weeks
AZD1480 significantly suppressed IL-6-driven prostate cancer metastasis in nude mice.
Mol Cancer Ther. 2014 May;13(5):1246-58.
Nude mice
Human GBM xenograft model
Intraperitoneal injection
30 mg/kg
Twice daily for 3 weeks
AZD1480 significantly inhibited the growth of subcutaneous tumors and increased the survival of mice bearing intracranial GBM tumors by inhibiting STAT-3 activity.
Mol Cancer Ther. 2011 Dec;10(12):2384-93.
Mice
Patient-derived xenograft (PDX) models
Oral
30 mg/kg
Twice daily, for 13 to 15 days
To evaluate the antitumor efficacy of AZD-1480 on HNSCC tumor growth, results showed that AZD-1480 significantly reduced tumor volume and decreased pSTAT3 Tyr705 expression
Neoplasia. 2015 Mar;17(3):256-64.
Mice
PANC1 subcutaneous xenograft model
Oral
30 mg/kg
5 days/week for 3 weeks
AZD1480 alone or in combination with gemcitabine significantly inhibited tumor growth and enhanced tumor drug delivery
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