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Bromodomain Inhibitor, (+)-JQ1

BET bromodomain inhibitor

Bromodomain Inhibitor, (+)-JQ1

Catalog No. A1910
Size Price Stock Qty
Evaluation Sample $28.00 In stock
5mg $80.00 In stock
10mg $150.00 In stock
50mg $500.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Product Citations

1. Li V C, Kirschner M W. Molecular ties between the cell cycle and differentiation in embryonic stem cells[J]. PNAS, 2014: 201408638.

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Chemical structure

JQ1

Related Biological Data

JQ1
ES cells were kept in 15% FBS media throughout the time course. Drug treatments were applied continuously at the designated concentrations for the entire duration of the time course, with daily media change. The effect of JQ1 is: a later suppression of MyoG expression.

Related Biological Data

JQ1
(+)-JQ1 shows potent inhibition of H4Kac4 binding. The IC50 value of 10nM for murine BRDT(1) and 11 nM for human BRDT(1). On the other hand, the (-)-JQ1 enantiomer was inactive for either ortholog

Related Biological Data

JQ1

Related Biological Data

JQ1

Biological Activity

Description (+)-JQ1 is an inhibitor of BET bromodomain with IC50 of 77 nM/33 nM for BRD4(1/2).
Targets BRD4(1/2)          
IC50 77 nM/33 nM          

Protocol

Cell experiment:[1]

Cell lines

Human Leukemia OCI-AML3 (AML-M4 subtype, DNMT3A-R882, NPM1c-mutated, p53-wildtype) cell lines

Preparation method

Dissolved in DMSO and stored at −20°C. Dilutions in PBS were used for experiments.

Reacting condition

0.25 μM JQ1 for 24 h incubation

Applications

BRD4 bromodomain inhibitor JQ1 is highly active against human leukemia OCI-AML3 mutation lines such as nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A). JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. JQ1 prevented BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner.

Animal experiment:[2]

Animal models

Male C57BL/6J (The Jackson Laboratory) and BALB/cJ (Charles River) mice, 6–8 wk of age

Dosage form

10% (w:v) JQ1 solution in 2-hydroxypropyl-β-cyclodextrin solvent (Sigma-Aldrich);

injected into the contralateral side of the abdomen

Applications

JQ1 ablated cytokine production and blunted the “cytokine storm” in endotoxemic mice by reducing levels of IL-6 and TNF-α while rescuing mice from LPS-induced death. JQ1 benefited hyper-inflammatory conditions associated with high levels of cytokine production.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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.

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Chemical Properties

Cas No. 1268524-70-4 SDF Download SDF
Chemical Name (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
Canonical 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
Formula C23H25ClN4O2S M.Wt 456.99
Solubility Soluble in DMSO Storage Store at -20°C
Shipping Condition: Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

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.

Background

Bromodomain Inhibitor, (+)-JQ1 is a potent and highly specific inhibitor for the BET (bromodomain and extra-terminal) family of bromodomains. (+)-JQ1 binds to BRD4 bromodomains 1 and 2 with Kd values of ~ 50 and 90 nM, respectively. The binding is competitive with acetyl lysine. (+)-JQ1 can be a useful chemical probe to investigate the role of BET bromodomains in the transcriptional regulation of oncogenesis.

JQ1 exhibited strong dose-and time- dependent inhibition of BRDT and could significantly diminish the activity of a close structural relative of BRDT. A close look at JQ1 bound BRDT confirmed that the acetyl-lysine recognition site of BRDT was blocked. [1]

JQ1 does not produce sedative or anxiolytic effects and is instead a potent and selective inhibitor of the bromodomain testis-specific protein BRDT [2], which is essential for chromatin remodeling during spermatogenesis. By blocking BRDT, JQ1 effectively blocks the production of sperm in the testes and consequently produces effective contraception, without the negative side effects associated with previously researched hormonal contraceptives for men.

References:
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.