A1910-1mg | Bromodomain Inhibitor, (+)-JQ1 [1268524-70-4] Clinisciences

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.

Product Citation

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Chemical Properties

Storage	Store at -20°C
M.Wt	456.99
Cas No.	1268524-70-4
Formula	C₂₃H₂₅ClN₄O₂S
Solubility	≥22.85 mg/mL in DMSO; insoluble in H2O; ≥55.6 mg/mL in EtOH
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
SDF	Download SDF
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
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment:[1]
Cell lines	Human Leukemia OCI-AML3 (AML-M4 subtype, DNMT3A-R882, NPM1c-mutated, p53-wildtype) cell lines
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	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.