生物活性

• 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. JAK2 is a member of the Janus family of cytoplasmic tyrosine kinases, with other members being JAK1, JAK3, and TYK. The normal function of JAK2 is to transmit signals following ligand binding of type I cytokine receptors, most notably the erythropoietin (EPO) and thrombopoietin receptors (MPL), the JAK2 _V617F mutation results in loss of inhibition of its tyrosine kinase activity, and therefore its continuous activity leads to increased signaling through the JAK-signal transducer and activator of transcription (STAT) pathway^[3]. XL019 is a potent and selective JAK2 inhibitor with IC₅₀ of 2.2 nM, exhibiting >50-fold selectivity over JAK1, JAK3 and TYK2. It has been studied in a phase 1 clinical trial but was forced to terminate due to CNS side effects. KBV20C cancer cells were stimulated for 72 h with 5 nM vincristine, 5 μM XL019, 5 nM vincristine with 5 μM XL019. XL019 reduced cellular viability and increased apoptosis in vincristine-treated KBV20C cells. The result demonstrated that XL019 can sensitize drug-resistant KBV20C cancer cells to vincristine treatment by reducing the proliferation of vincristine-treated KBV20C cells. XL019 also induced early apoptosis of KBV20C cells in response to vincristine treatment via increasing G2 phase arrest. Moreover, G2 phase arrest and apoptosis of cells co-treated with vincristine and XL019 resulted from the up-regulation of phosphorylated retinoblastoma protein (pRb), p21, and the DNA-damage protein, phosphorylated H2A histone family, member X (pH2AX)^[4].
• 作用机制The aniline substituted biarylpyrimidine core of XL019 can bind to the JAK2 binding site.
• 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
  NCT00522574	Myeloproliferative Disorders ... more >> Myelofibrosis Polycythemia Vera Thrombocythemia, Essential Collapse <<	Phase 1	Terminated(Due to emerging saf... more >>ety data) Collapse <<	-	United States, California ... more >> UCSF - Division of Hematology/Oncology San Francisco, California, United States, 94143 United States, Florida H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida, United States, 33612 United States, Massachusetts Dana Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, New York Mt. Sinai School of Medicine New York, New York, United States, 10029 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT00595829	Polycythemia Vera	Phase 1	Terminated	-	United States, California ... more >> UCLA School of Medicine, Center for Health Sciences Los Angeles, California, United States, 90095 UCSF - Division of Hematology/Oncology San Francisco, California, United States, 94143 United States, Florida H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida, United States, 33612 United States, Michigan University of Michigan Health System Ann Arbor, Michigan, United States, 48109 United States, New York Weill Cornell Medical College New York, New York, United States, 10065 Collapse <<

• 参考文献

• [1] Forsyth T, Kearney PC, et al. SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg Med Chem Lett. 2012 Dec 15;22(24):7653-8.

  [2] Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-42. doi: 10.1182/asheducation-2009.1.636.

  [3] Tam CS, Verstovsek S. Investigational Janus kinase inhibitors. Expert Opin Investig Drugs. 2013 Jun;22(6):687-99. doi: 10.1517/13543784.2013.774373. Epub 2013 Feb 23. PMID: 23432430.

  [4] Cheon JH, Kim JY, Lee BM, Kim HS, Yoon S. P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression. Anticancer Res. 2017 Dec;37(12):6761-6769. doi: 10.21873/anticanres.12136. PMID: 29187454.