生物活性

• 靶点

  Aurora Kinase A IC50:~3nM

  Aurora Kinase B IC50:~3nM

  Bcr-Abl (T315I) IC50:4nM

  JAK2 IC50:1.2nM

  JAK3 IC50:1.1nM

• 描述The Aurora family of serine/threonine kinases, which consists of Aurora A, B and C, plays an important role in chromosome alignment, segregation, and cytokinesis during mitosis. AT9283 is a multiple target inhibitor, most potent to JAK2/3 as well as Aurora A/B and Abl(T315I) with IC50 values of 1.2nM, 1.1nM, 3nM, 3nM and 4nM (measure by kinase assays), respectively, less potent to GSK-3β, FGFR2, VEGFR3/FLT4, Mer, RET, RSK2, RSK3, TYK2 and YES with IC50 ranging in 1-10nM^[1]. Treatment with AT9283 at concentration of 100nM for 2h resulted in endoreduplication, as well as a decrease in levels of phosphorylated histone H3 in HCT116 cells, indicating inhibition of Aurora B kinase. p53 induction and increased cleavage of PARP can be observed, followed ultimately by cell death by 14 days. The colony formation can be inhibited at dose of 7.7-20nM in a panel of tumor cell lines of different origins, including HCT116, HT-29, SW620, A2780, A549, MCF7 and MIA-Pa-Ca-2. Consistent with the in vitro study, a single of 10 mg/kg dose of AT9283 significantly decreased the level of phosphorylated histone H3 for up to 3h in tumor samples from HCT116 tumor bearing mice^[2]. Exposure to 1μM AT9283 caused a decrease in p-Stat5 1 h after the start of treatment, confirming inhibition of Jak2, as well as showed anti-proliferation with IC50 values ranging in 16-110nM in a number of Jak2-dependent cell lines, HEL, TF-1 and Ba/F3 ETV6-JAK2. AT9283 at dose of 10 mg/kg, bid, was efficacious in a Jak2-dependent murine leukemic model^[3]. Injection with AT9283 interperitoneally at dose of 15 and 20 mg/kg for 16 days produced a significant tumor growth inhibition of 67% (% T/C ) 33%) and 76% (% T/C ) 24%), respectively, in immunocompromised BALB/c nude mice bearing early stage HCT116 human colon carcinoma xenografts^[1].
• 作用机制For Aurora A, AT9283 can sit deeply in the ATP-binding site of Aurora A^[1]. For JAK2, AT9283 can bound to the active site of the Jak2 kinase domain^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A549 cells	-	Function assay	72 h	Antitumor activity against human A549 cells after 72 hrs by MTT assay, IC50=0.512 μM	23664099
  HCT116 cells	-	Cytotoxic assay	10-14 days	Cytotoxicity against human HCT116 cells assessed as number of colonies after 10 to 14 days by colony forming assay, IC50=0.012 μM	19143567
  HT-29 cells	-	Function assay	72 h	Antitumor activity against human HT-29 cells after 72 hrs by MTT assay, IC50=0.383 μM	23664099

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• 动物研究
  剂量	Mice: min = 15 mg/kg, max = 20 mg/kg[4]
  给药途径	i.p.

• 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
  NCT00985868	Unspecified Childhood Solid Tu... more >>mor, Protocol Specific Collapse <<	Phase 1	Active, not recruiting	December 2018	United Kingdom ... more >> Birmingham Children's Hospital Birmingham, England, United Kingdom, B4 6NH Leeds General Infirmary Leeds, England, United Kingdom, LS9 7TF Royal Manchester Children's Hospital Manchester, England, United Kingdom, M27 4HA Great North Children's Hospital, Royal Victoria Infirmary Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP Royal Marsden - Surrey Sutton, England, United Kingdom, SM2 5PT Collapse <<
  NCT01431664	Leukemia	Phase 1	Completed	-	United Kingdom ... more >> Royal Marsden Hospital Surrey, London, United Kingdom, SM2 5PT Birmingham Children's Hospital Birmingham,, United Kingdom, B4 6NH Leeds General Infirmary Leeds, United Kingdom, LS1 3EX Royal Manchester Children's Hospital Manchester, United Kingdom, M13 9WL Great North Children's Hospital, Royal Victoria Infirmary Newcastle upon Tyne, United Kingdom, NE1 4LP Collapse <<
  NCT00522990	Acute Myeloid Leukemia ... more >> Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia Myelodysplastic Syndromes Myelofibrosis Collapse <<	Phase 1 Phase 2	Terminated(Recommended Phase I... more >>I dose determined) Collapse <<	-	United States, Alabama ... more >> University of Alabama at Birmingham Birmingham, Alabama, United States, 35294 United States, Texas The University of Texas, MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<

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• 参考文献

• [1] Howard S, Berdini V, et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem. 2009 Jan 22;52(2):379-88.

  [2] Curry J, Angove H, et al. Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283. Cell Cycle. 2009 Jun 15;8(12):1921-9. Epub 2009 Jun 15.

  [3] Dawson MA, Curry JE, et al. AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. Br J Haematol. 2010 Jul;150(1):46-57.

  [4] Qi W, Liu X, et al. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer. 2012;130(12):2997-3005.