Bromodomain Inhibitor, (+)-JQ1 BET bromodomainYZ剂

Bromodomain Inhibitor, (+)-JQ1  BET bromodomainYZ剂 货号A1910
在人白血病OCI-AML3突变细胞系（比如核磷蛋白（NPM1）和DNA甲基转移酶3（DNMT3A））中，BRD4 bromodomain的YZ剂JQ1是高活性的，可引起caspase 3/7介导的细胞凋亡和DNA损伤响应。在OCI-AML3细胞中，JQ1阻止BRD4介导的p53在染色质靶标的聚集，导致细胞周期停滞和c-MYC非依赖性的细胞凋亡。化学性质

CAS号	1268524-70-4	SDF	Download SDF
化学名	(S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
SMILES	CC1=C(C)SC2=C1C(C3=CC=C(Cl)C=C3)=N[C@@H](CC(OC(C)(C)C)=O)C4=NN=C(C)N24
分子式	C23H25ClN4O2S	分子量	456.99
溶解性	>22.8mg/mL in DMSO	储存条件	Store at -20°C
运输条件	SY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	(+)-JQ1是一种BET bromodomainYZ剂，作用于BRD4（1/2），IC50值分别为77 nM/33 nM。
靶点	BRD4(1/2)
IC50	77 nM/33 nM

实验操作

细胞实验：
细胞系	人白血病OCI-AML3（AML-M4、DNMT3A-R882亚型、NPM1c突变、p53野生型）细胞系。
溶解方法	在DMSO中的溶解度>10 mM。为了获得更高的浓度，可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。
反应时间	0.25 μM JQ1；24小时
应用	在人白血病OCI-AML3突变细胞系（比如核磷蛋白（NPM1）和DNA甲基转移酶3（DNMT3A））中，BRD4 bromodomain的YZ剂JQ1是高活性的，可引起caspase 3/7介导的细胞凋亡和DNA损伤响应。在OCI-AML3细胞中，JQ1阻止BRD4介导的p53在染色质靶标的聚集，导致细胞周期停滞和c-MYC非依赖性的细胞凋亡。
动物实验：
动物模型	雄性C57BL/6J和BALB/cJ小鼠，6-8周龄。
剂量	10％（重量：体积）JQ1溶液，溶解在2-羟丙基β环糊精溶剂中；背部注射。
应用	在内毒素血症小鼠中，JQ1通过减少IL-6和TNF-α的水平，减少细胞因子的产生，防止LPS诱导的小鼠死亡。JQ1对与高水平细胞因子产生相关的超炎症性疾病有效果。
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]. Stewart HJ1, Horne GA, Bastow S et al. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. Cancer Med. 2013 Dec;2(6):826-35. [2]. Belkina AC1, Nikolajczyk BS, Denis GV. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J Immunol. 2013 Apr 1;190(7):3670-8.

View Related Products By Research Topics

• Cancer Biology
• BET
• Histone

研究更新
1. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. Cancer Med. 2013 Dec;2(6):826-35. doi: 10.1002/cam4.146. Epub 2013 Oct 31. 
Abstract 
JQ1 induces 3/7-mediated apoptosis and DNA damage response in p53-wild-type (OCI)-AML3 cell lines where it possibly sensitizes AML cells to p53-mediated cell death. A mechanism has been proposed that JQ1 is activated in OCI-AML3 cells preventing BRD4-mediated recruitment of p53 to chromatin targets and eventually leading to cell cycle arrest and apoptosis in a c-MYC-independent manner.
2. Affinity Map of BRD4 Interactions with the Histone H4 Tail and the Small Molecule Inhibitor JQ1. J Biol Chem. 2014 Feb 7. [Epub ahead of print] 
Abstract 
The affinities of acetylated histone tails and JQ1 to ten different BRD4 BD1 mutants were analyzed by several complementary biochemical and biophysical methods, in which W81, Y97, N140 and M149 play similarly important roles in the recognition of both.
3. Regulation of MYC Expression and Differential JQ1 Sensitivity in Cancer Cells. PLoS One. 2014 Jan 23;9(1):e87003. doi: 10.1371/journal.pone.0087003. eCollection 2014. 
Abstract 
JQ1, an inhibitor of MYC expression, exhibits different inhibition in tumor cells where it decreased ~90% MYC transcription in BL cells and exhibited lesser inhibition in several non-BL cells possibly due to requirements of Brd4, transcription factors (such as Gdown1 and MED26) and other unknown cell specific factors.
4. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J Immunol. 2013 Apr 1;190(7):3670-8. doi: 10.4049/jimmunol.1202838. Epub 2013 Feb 18. 
Abstract 
The critical role of BET proteins in macrophage inflammatory responses has been demonstrated in studies using small interfering RNA knockdown and JQ1 where Brad2 and brd4 doesn’t physically associated with the promoters of inflammatory cytokine genes in macrophages following the inhibition of BET by JQ1. JQ1 reduces the production of cytokine in vitro and weakens the “cytokine storm” in endotoxemic mice through decreasing IL-6 and TNF-α levels while rescuing mice from LPS-induced death.
5. The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic Acids Res. 2013 Jan 7;41(1):277-87. doi: 10.1093/nar/gks976. Epub 2012 Oct 18. 
Abstract 
JQ1 dissociates Brd4 from the HIV promoter, synergizes with another latency activator prostratin and activates viral latency without inducing global T cell activation, which allow it and other closely related compounds as well as their antagonization of Brd4 to be used as effective agents/strategies to eliminating latent HIV in further investigations.产品描述

(+)-JQ1是一种有效的、高特异性的BET bromodomainYZ剂。(+)-JQ1可以与乙酰赖an酸竞争结合BRD4 bromodomain 1和BRD4 bromodomain 2，Kd值分别为50和90 nM。(+)-JQ1可用于研究BET bromodomains在肿瘤发生中的转录调控作用。

JQ1是一种有效的、选择性的BRDT（bromodomain testis-specific protein）YZ剂。BRDT对精子发生过程中的染色质重组有重要作用。JQ1结合并YZBRDT，阻断乙酰赖an酸的识别位点，具有强烈的时间和剂量依赖性。通过阻断BRDT，JQ1有效地阻止了睾丸中精子的产生，从而可以有效的避孕。与之前研究的针对男性的激素避孕药相比，这种避孕药没有副作用。

参考文献： 
1. Matzuk, Martin M., et al. "Small-molecule inhibition of BRDT for male contraception." Cell 150.4 (2012): 673-684.
2.  Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.; Fedorov, O.; Morse, E. M.; Keates, T. et al. (2010). "Selective inhibition of BET bromodomains". Nature 468 (7327): 1067–1073.

引用文献

• 1.Deng W, Clipson A, et al."Variable Responses of MYC Translocation Positive Lymphoma Cell Lines To Different Combinations of Novel Agents: Impact of BCL2 Family Protein Expression." Transl Oncol. 2018 Jul 25;11(5):1147-1154. PMID:30055346
• 2.Kim SR, Lewis JM, et al. "BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition." Oncotarget.2018 Jun 26;9(49):29193-29207. PMID:30018745
• 3.Li N, Yang L, et al. "BET bromodomain inhibitor JQ1 preferentially suppresses EBV-positive nasopharyngeal carcinoma cells partially through repressing c-Myc." Cell Death Dis. 2018 Jul 9;9(7):761. PMID:29988031
• 4.Wang B, Chen G, et al. "A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters." Biomaterials. 2018 Jun 18;178:293-301. PMID:29958152
• 5.Pulikkan JA, Hegde M, et al."CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia." Cell. 2018 Jun 28;174(1):172-186.e21. PMID:29958106