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AT9283

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Chemical Structure| 896466-04-9 同义名 : -
CAS号 : 896466-04-9
货号 : A335492
分子式 : C19H23N7O2
纯度 : 99%+
分子量 : 381.432
MDL号 : MFCD12031513
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(275.28 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

2% DMSO+30% PEG 300+water 5 mg/mL

生物活性
靶点

  • JAK3

    JAK3, IC50:1.1 nM

  • Tyk2

    TYK2, IC50:1 nM-10 nM

  • JAK2

    JAK2, IC50:1.2 nM

  • Aurora A

    Aurora A, IC50:~3.0 nM
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
细胞系 浓度 检测类型 检测时间 活动说明 数据源
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
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... 展开 >>mor, Protocol Specific 收起 << Phase 1 Active, not recruiting December 2018 United Kingdom ... 展开 >> 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 收起 <<
NCT01431664 Leukemia Phase 1 Completed - United Kingdom ... 展开 >> 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 收起 <<
NCT00522990 Acute Myeloid Leukemia ... 展开 >> Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia Myelodysplastic Syndromes Myelofibrosis 收起 << Phase 1 Phase 2 Terminated(Recommended Phase I... 展开 >>I dose determined) 收起 << - United States, Alabama ... 展开 >> 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 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.62mL

0.52mL

0.26mL

13.11mL

2.62mL

1.31mL

26.22mL

5.24mL

2.62mL
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.