The JAK/STAT3 pathway is activated by various cancer types, including glioma, and blockade of the pathway induces cell death in cancer cells. Thus, the JAK/STAT3 pathway is a target for cancer therapy. WP1066 induces degradation of JAK2 and inhibition of its phosphorylation. WP1066 also degraded JAK2 protein, thereby blocking its downstream signal transducer and activator of transcription (STAT) and phosphoinositide-3-kinase pathways[3]. WP1066 is a most potent, small molecule, nonphosphorylated STAT3 inhibitor, that strongly binds to STAT3 protein with KD of 300 nM. The IC50 value in HEL cells is 2.3 μM[4]. In a vitro study, AML (acute myelocytic leukemia) cells obtained from the four patients with AML were cultured using the AML blast colony culture assay with or without WP1066 at concentrations ranging from 0.5 to 3.0 μM. The result showed that WP1066 inhibited the proliferation of AML blast colony-forming cells in a dose-dependent manner[5]. In a vivo study, mice with intracerebral melanoma were treated with WP1066 at a dose of 40 mg/kg for 21 days. The result showed that WP1066 could significantly increase the survival rate of intracerebral melanoma mice[6]. Use WP1066 at different concentrations from 0 to10 µM on SNK6 cells to demonstrate the influence of WP1066 on protein expression of p-STAT3 and downstream molecules. The decrease of protein expression for p-STAT3 in SNK6 cells after a 24-h treatment of WP1066 in a dose-dependent manner which indicated the inhibition of the pro-survival factors downstream of STAT3 pathway may be the potential mechanisms contributing to the antitumor effect of WP1066 in nasal NKTCL(Nasal-type natural killer/T-cell lymphoma) cells[7].
作用机制
WP1066 can strongly bind to STAT3 protein and bind to the enzyme pocket of JAK2.
WP1066 细胞实验
Cell Line
Concentration
Treated Time
Description
References
B16 cells
0, 0.156, 0.313, 0.625, 1.25, 2.5, 5.0 µM
72 h
To evaluate the direct cytotoxic effects of WP1066 on B16 cells, results showed that WP1066 enhanced tumor cytotoxicity when combined with CTX.
Int J Cancer. 2012 Jul 1;131(1):8-17.
B16 cells
2.5 µM, 5 µM
2 h
To evaluate the inhibitory effect of WP1066 combined with CTX on p-STAT3, results showed that CTX enhanced the inhibition of p-STAT3 by WP1066.
Int J Cancer. 2012 Jul 1;131(1):8-17.
D283-Med cells
10 µM
48 h
To evaluate the effect of WP1066 on the STAT3 signaling pathway, results showed that WP1066 significantly reduced the expression of p-STAT3 and c-MYC.
Acta Neuropathol. 2021 Sep;142(3):537-564.
CT2A cells
10 μM
To verify the effect of STAT3 inhibitor WP1066 on CT2A cells, results showed that WP1066 treatment reduced YAP1 expression.
Nat Commun. 2024 Mar 5;15(1):1987.
GL261 cells
10 μM
To verify the effect of STAT3 inhibitor WP1066 on GL261 cells, results showed that WP1066 treatment reduced YAP1 expression.
Nat Commun. 2024 Mar 5;15(1):1987.
GSC272 cells
10 μM
To verify the effect of STAT3 inhibitor WP1066 on GSC272 cells, results showed that WP1066 treatment reduced YAP1 expression.
Nat Commun. 2024 Mar 5;15(1):1987.
PANC-1 cells
5 μM
24 h
To study the inhibitory effect of WP1066 on the STAT3 signaling pathway, results showed that WP1066 effectively inhibited STAT3 activation and reduced LOXL2 expression.
Neoplasia. 2025 Feb;60:101096.
SW1990 cells
5 μM
24 h
To study the inhibitory effect of WP1066 on the STAT3 signaling pathway, results showed that WP1066 effectively inhibited STAT3 activation and reduced LOXL2 expression.
Neoplasia. 2025 Feb;60:101096.
GL261 cells
0, 1.56, 3.13, 6.25, 12.5, 25 μM
72 h
To evaluate the effect of WP1066 on the proliferation and survival of GL261 cells, and to calculate the IC50 value.
Clin Cancer Res. 2020 Sep 15;26(18):4983-4994.
hepatocytes
5 μM
24 h
To evaluate the inhibitory effect of WP1066 on STAT3 phosphorylation, the results showed that WP1066 significantly inhibited STAT3 phosphorylation.
JCI Insight. 2022 Jun 16;7(14):e158207.
KYSE30
5 μM
20 h
To investigate the effect of WP1066 on STAT3-mediated EMT in MAGE-C3 overexpressing KYSE30 cells. Results showed that WP1066 treatment attenuated the promotion of migration and invasion by MAGE-C3.
Cancer Commun (Lond). 2021 Dec;41(12):1354-1372.
KYSE410
5 μM
20 h
To investigate the effect of WP1066 on STAT3-mediated EMT in MAGE-C3 overexpressing KYSE410 cells. Results showed that WP1066 treatment attenuated the promotion of migration and invasion by MAGE-C3.
Cancer Commun (Lond). 2021 Dec;41(12):1354-1372.
WP1066 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
Intracerebral B16 melanoma model
Oral
30 mg/kg
Once every other day for 9 treatments
To evaluate the therapeutic efficacy of WP1066 combined with CTX against intracerebral melanoma, results showed that the combination significantly prolonged the survival of mice.
Int J Cancer. 2012 Jul 1;131(1):8-17.
Mice
Ischemic stroke model
Intraperitoneal injection
30 mg/kg
Once daily for 5 days
WP1066, as a STAT3 inhibitor, was used to study its neuroprotective effects in the ischemic stroke model. The results showed that WP1066 suppressed Li+-induced activation of STAT3, thereby affecting UCP2 expression and ROS production.
Commun Biol. 2022 Feb 3;5(1):105
Rats
Pilocarpine-induced status epilepticus model
Intraperitoneal injection
50 mg/kg
Two doses, 45 minutes apart
WP1066 transiently inhibits pSTAT3 after the onset of status epilepticus and reduces long-term spontaneous seizure frequency, but does not affect status epilepticus or cell death.
Neurobiol Dis. 2014 Feb;62:73-85
NOD scid gamma mice
MBGroup3 mouse model
Intraperitoneal injection
30 mg/kg
Every other day for 24 days
To evaluate the effect of combined treatment with WP1066 and CQ on the MBGroup3 mouse model, results showed that the combined treatment significantly extended the survival of mice.
Acta Neuropathol. 2021 Sep;142(3):537-564.
Mice
CT2A tumor model
Oral
60 mg/kg
Every other day for 6 doses
To verify the effect of STAT3 inhibitor WP1066 on the CT2A tumor model, results showed that WP1066 treatment reduced plasma levels of CCL2 and CCL7 and decreased intratumoral macrophages.
Nat Commun. 2024 Mar 5;15(1):1987.
C57BL/6 mice
GL261 glioma model
Oral gavage
60 mg/kg
Monday, Wednesday, Friday for 3 weeks
To evaluate the therapeutic effect of WP1066 combined with whole-brain radiation therapy (WBRT) on glioma, the results showed that the combination therapy significantly prolonged the survival of mice and induced immunological memory.
United States, Texas
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M D Anderson Cancer Center
Recruiting
Houston, Texas, United States, 77030
Contact: Amy B. Heimberger 713-563-8717
Principal Investigator: Amy B. Heimberger 收起 <<
United States, Texas
... 展开 >>
M D Anderson Cancer Center
Recruiting
Houston, Texas, United States, 77030
Contact: Amy B. Heimberger 713-563-8717
Principal Investigator: Amy B. Heimberger 收起 <<
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