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OTX-015

现货
Catalog No.
A3692
BRD抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,400.00
现货
5mg
¥ 1,300.00
现货
10mg
¥ 1,890.00
现货
50mg
¥ 5,000.00
现货
100mg
¥ 8,500.00
现货

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Background

OTX-015 is a potent inhibitor of BRD2, BRD3, and BRD4 with IC50 values range from 92 to 112 nM [1].
BRD2, BRD3, and BRD4 belong to BET bromodomain family and play an important role in regulating transcription. BRDs regulate several oncogenes transcription in a variety of cancers and thus have emerged as a promising target [2].
OTX-015 is a selective BRD2, BRD3, and BRD4 inhibitor and inhibits the binding of BRD2, BRD3, and BRD4 to AcH4. Using TR-FRET method and CHO cell lysate harboring BRD2, BRD3, and BRD4 to research the effect of OTX-015, result showed that OTX-015 inhibited BET family binding to AcH4 in a dose-dependent manner and the EC50 values range from 10 to 19 nM. When tested with human tumor cell lines, incubation with OTX-015 for 72 hours inhibited cell proliferation with GI 50 values ranged from 60 to 200 nM [1]. In ALKpos ALCL cell lines, treatment of OTX-015 for 24 h arrested cell proliferation in G1 phase which was more pronounced at 48 h and 72 h, and tested with SUPM2/TS and JB-6 cell lines OTX-015 showed ability to increase cell death rate [3].
In BLAB/c-nu/nu mice model with established Ty82 BRD-NUT midline carcinoma xenografts, oral administration of OTX-015 markedly inhibited tumor growth and reduced tumor volume [1].
References:
[1]. J. Kay Noel, Kazunori Iwata, Shinsuke Ooike, et al. Development of the BET bromodomain inhibitor OTX015 [J]. Mol Cancer Ther November 2013 12; C244.
[2]. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery [J]. Oncotarget. 2015 Mar 20;6(8):5501-5516.
[3]. Michela Boi, Maria Todaro, Valentina Vurchio, et al. OTX015, a bromodomain and extraterminal inhibitor, represents a novel agent for ALK positive anaplastic large cell lymphoma [J]. Mol Cancer Ther November 2013 12; A219.

文献引用

1. Zhao M, De Crignis E, et al. "T cell toxicity of HIV latency reversing agents." Pharmacol Res. 2018 Oct 23. pii: S1043-6618(18)30970-8. PMID:30366100
2. Qian G, Yao W, et al. "Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy. Cancer Lett. 2018 Oct 28;435:44-54. PMID:30059709
3. Abner E, Stoszko M, et al. "A new quinoline BRD4 inhibitor targets a distinct latent HIV-1 reservoir for re-activation from other 'shock' drugs." J Virol. 2018 Jan 17. pii: JVI.02056-17. PMID:29343578

Chemical Properties

StorageStore at -20°C
M.Wt491.99
Cas No.202590-98-5
FormulaC25H22ClN5O2S
SynonymsOTX 015;OTX015
Solubility≥24.6 mg/mL in DMSO, ≥106 mg/mL in EtOH with gentle warming, <2.38 mg/mL in H2O
SDFDownload SDF
Canonical SMILESCC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NC4=CC=C(C=C4)O)C5=CC=C(C=C5)Cl)C
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

结合实验

为了评估OTX015与BRD2、BRD3和BRD4的结合,将表达BRD的CHO细胞裂解物(转染表达Flag-tagged BRD2、BRD3、BRD4或载体质粒的CHO细胞)、铕共轭的抗Flag抗体、XL-665缀合的链霉素和生物素化的OTX015在室温下温育0.2至2小时。使用EnVision 2103 Multilabel Reader通过TR-FRET测量荧光,使用PRISM 5.02通过非线性回归计算结合的EC50。使用类似的系统,通过孵育生物素化AcH4、表达BRD的CHO细胞裂解物、铕缀合的抗Flag抗体以及XL-665缀合的链霉素,评价OTX015对BRD2、BRD3和BRD4与乙酰化组蛋白H4(AcH4)结合的效应。将没有生物素偶联物dAcH4的样品值定义为0%,将没有OTX015的样品值定义为100%,使用EnVision 2103 Multilabel Reader通过TR-FRET测量荧光,计算结合百分比。使用PRISM5.02版本通过非线性回归计算IC50值。

细胞实验[1]:

细胞系

人肿瘤细胞

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月

反应条件

72 h.

实验结果

OTX-015抑制多种人癌细胞系的生长。对于所测试的大多数血液恶性肿瘤,OTX-015抑制生长的GI50值为60-200 nM。

动物实验[1]:

动物模型

Ty82 BRD-NUT中线癌肿瘤异种移植BLAB/c-nu/nu小鼠

剂量

0、10、30或100 mg/kg每日1次或10 mg/kg每日2次;14天;口服。

实验结果

OTX015显著抑制肿瘤生长,100 mg/kg qd和10 mg/kg bid时TGI分别为79%和61%。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. J. Kay Noel, Kazunori Iwata, ShinsukeOoike, et al. Development of the BET bromodomain inhibitor OTX015 [J]. Mol Cancer Ther, 2013, 12(11 Suppl): C244.

生物活性

描述 OTX-015是一种可口服的bromodomain and extra terminal domain (BET)家族蛋白小分子抑制剂,作用于BRD2、BRD3和BRD4,EC50范围介于10-19 nM之间。
靶点 BRD2 BRD3 BRD4      
IC50            

质量控制

化学结构

OTX-015

相关生物数据

OTX-015

相关生物数据

OTX-015

相关生物数据

OTX-015