The JAK/STAT3 pathway is activated by various cancer types, including glioma, and blockade of the pathway induces cell death in cancer cells. JAKs encompass a family of four (JAK1, JAK2, JAK3 and TYK2) intracellular, non-receptor tyrosine kinases, associated with cytokine receptors. Under normal conditions, activation of the receptor by cytokine binding leads to trans-phosphorylation of JAK and downstream phosphorylation of STAT proteins (pSTAT)[3]. JAK2 phosphorylates cell surface receptors on tyrosine residues creating docking sites for STAT3 proteins. Once STAT3 is recruited to the receptor, it is phosphorylated by JAK2 allowing STAT3 to form a dimer and move into the nucleus where it can activate the transcription of target genes[4]. Pacritinib is a JAK2 and fms-like tyrosine kinase-3 (FLT3) inhibitor with IC50 23 nM and 22 nM. It also suppresses the interleukin-1-directed inflammatory pathway via inhibition of interleukin 1 receptor-associated kinase 1 (IRAK1)[5]. In a phase I study, thirteen AML (acute myeloid leukemia) patients were enrolled, treated with Pacritinib at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin or with decitabine induction. The result demonstrated that pacritinib was well tolerated and had preliminary anti-leukemic activity[6]. In a vivo study, the Stelic animal model (STAM) mouse were given 200 mg/kg Pacritinib orally for twice a day for 10 days. Pacritinib-treated mice had significantly reduced fibrotic areas in liver compared to vehicle control and significantly lower levels of CK18 which demonstrated that pacritinib possess a good antifibrotic effect[7]. Thirty-two mice were xenografted with BT147(brain tumor initiating cells) cells, and treated with pacritinib at a dose of 100 mg/kg. Pacritinib resulted in an increase median survival of 62.5 days which demonstrated pacritinib synergy with TMZ may be another considerable choice therapy for GBM(glioblastoma multiforme)[4].
作用机制
Pacritinib can bind with the JAK2 enzyme binding pocket.
Pacritinib/帕克替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Hepatic Stellate Cells (HSCs)
1 µM
24 hours
Pacritinib reduced gene expression of fibrosis markers and decreased proliferation and contraction of HSCs.
Hepatology. 2023 Apr 1;77(4):1228-1240.
Breast cancer cell lines
0.1-10 µM
Pacritinib reduced cell viability and promoted apoptosis in breast cancer cells.
Cancer Lett. 2024 Aug 10;597:217023.
Pacritinib/帕克替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
CCl4 and ethanol-induced liver fibrosis
Oral
300 mg/kg
Three times per week for 3 weeks
Pacritinib treatment reduced liver fibrosis and liver injury.
Hepatology. 2023 Apr 1;77(4):1228-1240.
Mice
TNBC PDX model
Oral
50 mg/kg
Twice daily for 5 days/week until study termination
Pacritinib effectively suppressed tumor growth in vivo.
United States, Washington
... 展开 >>
Fred Hutch/University of Washington Cancer Consortium
Recruiting
Seattle, Washington, United States, 98109
Contact: Rachel B. Salit 206-667-1317 rsalit@fredhutch.org
Principal Investigator: Rachel B. Salit 收起 <<
United States, Washington
... 展开 >>
Fred Hutch/University of Washington Cancer Consortium
Recruiting
Seattle, Washington, United States, 98109
Contact: Rachel B. Salit 206-667-1317 rsalit@fredhutch.org
Principal Investigator: Rachel B. Salit 收起 <<
United States, Florida
... 展开 >>
H. Lee Moffitt Cancer Center and Research Institute
Recruiting
Tampa, Florida, United States, 33612
Principal Investigator: Joseph Pidala, M.D.
Sub-Investigator: Melissa Alsina, M.D.
Sub-Investigator: Marco Davila, M.D., Ph.D.
Sub-Investigator: Linda Kelley, Ph.D.
Sub-Investigator: Farhad Khimani, M.D.
Sub-Investigator: Frederick Locke, M.D.
Sub-Investigator: Asmita Mishra, M.D.
Sub-Investigator: Taiga Nishihori, M.D.
Sub-Investigator: Jose Ochoa-Bayona, M.D.
Sub-Investigator: Lia Perez, M.D.
Sub-Investigator: Hugo Fernandez, M.D, 收起 <<
United States, Ohio
... 展开 >>
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210 收起 <<
Germany
... 展开 >> APEX GmbH
Munich, Germany, D-81241
Moldova, Republic of
Republican Clinical Hospital
Chisinau, Moldova, Republic of, MD-2025
Romania
Carol Davila Nephrology Hospital Bucharest
Bucharest, Romania 收起 <<
Withdrawn(FDA has placed all t... 展开 >>rials involving Pacritinib on Full Clinical Hold) 收起 <<
October 2018
United States, Michigan
... 展开 >>
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905 收起 <<
Terminated(The study was put o... 展开 >>n clinical hold by the sponsor since Feb 9th 2016, and was later decided not to re-open due to financial constraints.) 收起 <<
-
United States, New York
... 展开 >>
Weill Cornell Medical College
New York, New York, United States, 10021 收起 <<
Terminated(The study was put o... 展开 >>n clinical hold by the sponsor since Feb 9th 2016, and was later decided not to re-open due to financial constraints.) 收起 <<
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