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SNS-032 (BMS-387032)CDK抑制剂

SNS-032 (BMS-387032)

产品编号:A1980
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Sample solution is provided at 25 µL, 10mM.

引用文献

1. Cingöz O, Goff SP. "Cyclin-dependent kinase activity is required for type I interferon production." Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):E2950-E2959. PMID:29507205
2. Posternak V, Ung MH, et al. "MYC Mediates mRNA Cap Methylation of Canonical Wnt/β-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase." Mol Cancer Res. 2017 Feb;15(2):213-224. PMID:27899423

质量控制

化学结构

SNS-032 (BMS-387032)

相关生物数据

SNS-032 (BMS-387032)

相关生物数据

SNS-032 (BMS-387032)

相关生物数据

SNS-032 (BMS-387032)

相关生物数据

SNS-032 (BMS-387032)

SNS-032 (BMS-387032) Dilution Calculator

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SNS-032 (BMS-387032) Molarity Calculator

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化学性质

CAS号 345627-80-7 SDF Download SDF
化学名 N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide
SMILES CC(C)(C)C1=CN=C(O1)CSC2=CN=C(S2)NC(=O)C3CCNCC3
分子式 C17H24N4O2S2 分子量 380.53
溶解度 ≥19.05mg/mL in DMSO 储存条件 Store at -20°C
物理性状 A solid 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。

生物活性

描述 SNS-032是一种选择性的CDK2抑制剂,IC50值为38 nM。
靶点 CDK2 CDK7 CDK9      
IC50 48 nM 62 nM 4 nM      

实验操作

细胞实验 [1]:

细胞系

慢性淋巴细胞白血病(CLL)细胞

制备方法

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

0.1 μM、0.3 μM和1 μM;6小时或24小时

试验结果

在CLL细胞中,给予SNS-032,持续6小时或24小时,呈时间和浓度依赖性地减少了RNA聚合酶II CTD Ser5和Ser2磷酸化,而且样品间无显著差异。相对于Ser5磷酸化,SNS-032对Ser2磷酸化的抑制作用较大。相应地,SNS-032对 CDK9的IC50值与SNS-032对CDK7的IC50值相比,相对较低(4 nM:62 nM)。给予SNS-032,6小时后,CDK7和CDK9蛋白水平稳定,但在24小时下降。

动物实验 [2]:

动物模型

MDA-MB-435细胞异种移植小鼠模型

给药剂量

15 mg/kg;腹腔注射;每3天1次,持续约1个月

实验结果

给予SNS-032,给药30天后(共注射了8针SNS-032),SNS-032显著抑制异种移植乳腺肿瘤的体积(65.77%)。

其他注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Chen R., Wierda W.G., Chubb S., et al. Mechanism of action of SNS032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood, 2009, 113(19):4637-4645.

[2]. Xie G, Tang H, Wu S, Chen J, Liu J, Liao C. The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. Int J Oncol. 2014 Aug;45(2):804-12.

研究更新

1. Testing of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of Drugs. Transl Oncol. 2013 Dec 1;6(6):685-96. eCollection 2013.
Abstract
SNS-032, a CDK inhibitor, exhibited modest to high anti-neuroblastoma activity against a panel of 109 neuroblastoma cell lines in the range of the therapeutic plasma levels reported for SNS-032 through a mechanism involving CDK7 and CDK9 inhibition-mediated down-regulation of XIAP, Mcl-1, BIRC2, cIAP-1 and surviving.
2. SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt. J Hematol Oncol. 2013 Feb 18;6:18. doi: 10.1186/1756-8722-6-18.
Abstract
The anti-AML mechanism of SNS-032, a cyclin-dependent kinase inhibitor, has been identified though characterizing in vitro effects of SNS-032 alone or in combination with perifosine.
3. [Effect of SNS-032 on biological activity of hematopoietic stem cells in mice]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013 Jun;21(3):741-5. doi: 10.7534/j.issn.1009-2137.2013.03.040.
Abstract
Although it induces apoptosis in cancer cells, SNS-032 has no significant effects on normal HSC and HPC in terms of self-renewal inhibition, differentiation suppression and apoptosis induction.
5. The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine. Leukemia. 2011 Mar;25(3):411-9. doi: 10.1038/leu.2010.290. Epub 2011 Jan 7.
Abstract
SNS-032, a CDK inhibitor, alone or in combination with Ara-C exhibited potent anti-AML activity, where down-regulation of antiapoptotic genes, cluding BCL2, XIAP amd MCL1, was associated with the synergistic anti-AML effect of the combination treatment.

产品描述

SNS-032(BMS-387032)是一种有效的和选择性的细胞周期蛋白依赖性激酶(CDKs)2、7和9的抑制剂[1],IC50值分别为38 nM、62 nM和4 nM[2]。

CDKs属于丝氨酸/苏氨酸激酶家族,调节细胞周期进程。有些CDKs与转录调控相关,在癌细胞中经常被扰动[3]。

RNA聚合酶II的C-端结构域(CTD)Ser5和Ser2磷酸化的减少表明CDK9和CDK7的抑制[1]。在慢性淋巴细胞白血病(CLL)细胞中,SNS-032处理6小时或24小时后导致RNA聚合酶II的C-端结构域(CTD)Ser2和Ser5磷酸化的减少,这种效应是时间和浓度依赖的,且在不同的样品中极其一致。SNS-032对Ser2磷酸化的抑制作用要强于对Ser5磷酸化的抑制,这与以下事实一致,即SNS-032抑制CDK9的IC50值要低于抑制CDK7的IC50值,分别为4 nM和62 nM。在6小时的处理后,CDK7和CDK9的蛋白水平是稳定的,而在24小时的处理后,两者均下降[4]。

在慢性淋巴细胞白血病(CLL)患者中,SNS-032以75 mg/m2的总剂量注射后导致RNA聚合酶II的C-端结构域(CTD)Ser5和Ser2磷酸化的减少,这表明SNS-032对Cdk9和Cdk7的抑制,这种抑制作用在SNS-032开始注射后的2小时出现,6小时后是明显的,而在24小时后回到基线水平[1]。

参考文献:
[1].  Tong W.G., Chen R., Plunkett W., et al. Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma. Journal of Clinical Oncology, 2010, 28(18):3015- 3022.
[2].  Chipumuro E., Marco E., Christensen C.L., et al. CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer. Cell, 2014, 159:1-14.
[3].  Meng H., Jin Y.M., Liu H., et al. SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt. Journal of Hematology & Oncology, 2013, 6:18.
[4].  Chen R., Wierda W.G., Chubb S., et al. Mechanism of action of SNS032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood, 2009, 113(19):4637-4645.