生物活性

• 靶点

  FLT3 IC50:22nM

  JAK1 IC50:1280nM

  JAK2 IC50:23nM

  JAK2 (V617F) IC50:19nM

  JAK3 IC50:520nM

• 描述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.
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02251821	Primary Myelofibrosis ... more >> Secondary Myelofibrosis Collapse <<	Phase 2	Recruiting	-	United States, Washington ... more >> 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 Collapse <<
  NCT02823171	Healthy	Phase 1	Completed	-	United States, Indiana ... more >> Covance Clinical Research Unit Inc. Evansville, Indiana, United States, 47710 Collapse <<
  NCT02342353	Non-Small Cell Lung Cancer ... more >> Nonsmall Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Collapse <<	Phase 1	Terminated(Drug shortage)	-	United States, Missouri ... more >> Washington University School of Medicine Saint Louis, Missouri, United States, 63110 Collapse <<

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