(+)-JQ1

Alias: Bromodomain Inhibitor; (+)-JQ 1; (+)-JQ-1; (+)-JQ1;
Cat No.:V0411 Purity: ≥98%
(+)-JQ1 is a novel, potent and highly specific BET (Bromodomain and extra terminal domain) bromodomain inhibitor with antineoplastic activity.
(+)-JQ1 Chemical Structure CAS No.: 1268524-70-4
Product category: Epigenetic Reader Domain
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of (+)-JQ1:

  • (-)-JQ-1
  • (+)-JQ1 carboxylic acid
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Top Publications Citing lnvivochem Products
InvivoChem's (+)-JQ1 has been cited by 1 publication
Purity & Quality Control Documentation

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Product Description

(+)-JQ1 is a novel, potent and highly specific BET (Bromodomain and extra terminal domain) bromodomain inhibitor with antineoplastic activity. It inhibits BRD4(1/2) with an IC50 of 77 nM and 33 nM in enzymatic assays. It has high specificity for BET in that it only binds to bromodomains of the BET family, but not to any bromodomains of non-BET family. (+)-JQ1 has potential antineoplastic activity against various cancers such as MM (Multiple myeloma), pancreatic ductal adenocarcinoma and ovarian cancer etc. Its mechanism of action is to inhibit c-MYC and upregulate p21. (+)-JQ1 has been used as a chemical probe to investigate the role of BET bromodomains in the transcriptional regulation of oncogenesis.

Biological Activity I Assay Protocols (From Reference)
Targets
BRD4 (1/2) (IC50= 77/33 nM)
ln Vitro
(+)-JQ-1 represents a strong, highly selective and Kac-competitive inhibitor of the bromodomain BET family. (+)-JQ-1 (100 nM, 48 h) increases squamous development, evidenced by cell spindle formation, flattening, and enhanced keratin expression. (+)-JQ-1 (250 nM) stimulates fast expression of keratin in treated NMC 797 cells compared to (-)-JQ1 (250 nM) and vehicle control, as evaluated by quantitative immunohistochemistry of. (+)-JQ-1 (relative to (-)-JQ1 (250 nM)) causes time-dependent strong (3+) keratin staining in treated NMC 797 cells [1]. Derepression of autophagy genes was seen almost immediately upon addition of (+)-JQ-1 [2]. (+)-JQ-1 is a strong thiophenediazepine inhibitor (Kd=90 nM) of the BET family coactivator protein BRD4, which participates in the development of cancer through the transcriptional regulation of the MYC oncogene. Dose-ranging experiments of (+)-JQ-1 indicated efficient suppression of H4Kac4 binding, with IC50 values of 10 nM for mouse BRDT (1) and 11 nM for human BRDT (1) [3].
ln Vivo
Matching mouse cohorts with tumors that had already developed were randomized to receive intraperitoneal injections of either vehicle or (+)-JQ1 (50 mg/kg) every day. FDG-PET imaging was used to assess the mice both four days post-treatment and before to randomization. FDG uptake was shown to be significantly reduced when (+)-JQ1 was administered. Tumor growth was inhibited by JQ1 treatment, as demonstrated by assessments of tumor volume. CD1 mice were used for pharmacokinetic studies of (+)-JQ1 following oral and intravenous dosing. Time profile of the mean plasma concentration of (+)-JQ1 following intravenous injection (5 mg/kg). The half-life (T1/2) of intravenous (+)-JQ1 was approximately one hour, and its pharmacokinetic characteristics demonstrated good drug exposure (AUC=2090 hr*ng/mL). After oral dosage (10 mg/kg), a mean plasma concentration-time profile of (+)-JQ1 was created. Oral (+)-JQ1 pharmacokinetic parameters showed good drug exposure (AUC=2090 hr*ng) /mL), peak plasma concentration (Cmax=1180 ng/mL), and oral bioavailability (F=49%)[1].
Enzyme Assay
Acetyl-Histone Binding Assay. [1]
Assays were performed as described previously51 with minor modifications from the manufacturer’s protocol (PerkinElmer, USA). All reagents were diluted in 50 mM HEPES, 100 mM NaCl, 0.1 % BSA, pH 7.4 supplemented with 0.05 % CHAPS and allowed to equilibrate to room temperature prior to addition to plates. A 24-point 1:2 serial dilution of the ligands was prepared over the range of 150 – 0 μM and 4 μl transferred to low-volume 384-well plates, followed by 4 μl of His-tagged protein (BRD4(1), 250 nM, BRD4(2) and CREBBP, 2000 nM). Plates were sealed and incubated at room temperature for 30 minutes, before the addition of 4 μl of biotinylated peptide at equimolar concentration to the protein [peptide for BRD4(1) & BRD4(2): H4K5acK8acK12acK16ac, HSGRGK( Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRK(Biotin)-OH; peptide for CREBBP: H3K36ac, Biotin-KSAPATGGVK(Ac)KPHRYRPGT-OH]. Plates were sealed and incubated for a further 30 minutes, before the addition of 4 μl of streptavidin-coated donor beads (25 μg/ml) and 4 μl nickel chelate acceptor beads (25 μg/ml) under low light conditions. Plates were foil-sealed to protect from light, incubated at room temperature for 60 minutes and read on a PHERAstar FS plate reader using an AlphaScreen 680 excitation/570 emission filter set. IC50 values were calculated in Prism 5 (GraphPad Software, USA) after normalization against corresponding DMSO controls and are given as the final concentration of compound in the 20 μl reaction volume.
Cell Assay
Cell Proliferation Assay. [1]
Cells were seeded into white, 384-well microtiter plates (Nunc) at 500 cells per well in a total volume of 50 μl media. The 797, TT and TE10 cells were grown in DMEM containing 1 % penicillin/streptomycin and 10 % FBS. The Per403 cells were grown in DMEM containing 1 % penicillin/streptomycin and 20 % FBS. Patient-derived NMC 11060 cells were grown in RPMI with 10 % FBS and 1% penicillin/streptomycin. Compounds were delivered to microtiter assay plates by robotic pin transfer (PerkinElmer JANUS equipped with a V&P Scientific 100 nl pin tool). Following a 48 h incubation at 37 ºC, cells were lysed and wells were assessed for total ATP content using a commercial proliferation assay. Replicate measurements were analyzed with respect to dose and estimates of IC50 were calculated by logistic regression. [1]

Cell Growth Assay.[1]
Cells were seeded in 6-well tissue culture dishes at a concentration of 1.5 x 104 cells per well. Cells were grown in 2 ml of either DMEM (797) or RPMI (11060) containing 10 % fetal bovine serum, 1 % penicillin/streptomycin and either 250 nM (+)-JQ1 or the equivalent volume of DMSO (0.025 %). One half of the media in each well was replaced daily. On days 0, 1, 3, 7 and 10, dishes of cells assigned to each time point were trypsinized, mixed in a 1:1 ratio with 0.4 % trypan blue and counted using a Countess automated cell counter.
Animal Protocol
Xenograft Efficacy Studies.[1]
NMC 797 xenografts were established by injecting NMC 797 cells (107) in 30 % Matrigel (BD Biosciences) into the flank of 6 week-old female NCr nude mice. Twelve days after injection, mice with measureable tumors were divided into cohorts to be treated with JQ1 at 50 mg kg-1 IP or vehicle (5 % DMSO in 5 % dextrose). For FDG-PET studies, mice with established tumors measuring approximately 1 cm in the largest linear dimension underwent baseline CT/PET imaging 1 h after injection of 250 μCi of FDG (Pre-treatment). Mice were then treated with four daily doses of 50 mg kg-1 of racemic JQ1 by intraperitoneal injection. Two hours after the fourth dose of JQ1 or vehicle, mice underwent repeat FDG-PET imaging (Post-treatment). The integrated signal encompassed within the entire tumor volume is expressed as the percent of injected dose per gram (% ID/gm). Tumors were fixed in 10 % buffered formalin for histopathological analysis. For tumor caliper studies, the average size of tumors in the JQ1 treatment group (n = 8) and vehicle group (n = 7) were similar (63.8 ± 17.1 and 73.6 ± 14.4 mm3 respectively) at the start of treatment. Animals were followed daily for clinical symptoms. Tumor measurements were assessed by caliper measurements, and volume calculated using the formula Vol = 0.5 x L x W2. After 2 weeks of treatment, all mice were humanely euthanized, and tumors were fixed in 10 % formalin for histopathological examination. Statistical significance of tumor volumes was calculated by two-sided Students t-test.[1]

Primary NMC Xenograft Studies.[1]
A primary xenograft model of NMC was established by injecting NCr nude mice with primary cells (107 cells in 100 μl of 30 % Matrigel in 70 % PBS) collected from malignant pleural fluid obtained with IRB approval and informed consent from a patient at the Dana-Farber Cancer Institute and Brigham & Women’s Hospital. As above, four mice with established tumors measuring approximately 1 cm in the largest linear dimension underwent baseline CT/PET imaging 1 h after injection of 250 μCi of FDG (Pre-treatment). Mice were then treated with four daily doses of 50 mg kg-1 of (+)-JQ1 by intraperitoneal injection. Animals were followed daily for clinical symptoms. Two hours after the fourth dose of (+)-JQ1 or vehicle, mice underwent repeat FDG-PET imaging (Post-treatment). The integrated signal encompassed within the entire tumor volume is expressed as the percent of injected dose per gram (%ID/gm). Tumors were fixed in 10 % buffered formalin for histopathological analysis. At the conclusion of the study, all mice were humanely euthanized, and tumors were fixed in 10 % formalin for histopathological examination. Survival (30 days) studies performed with NMC Per403 and 11060 xenografts were initiated as above. For these studies, (+)-JQ1 was administered at a dose of 50 mg kg-1 by daily intraperitoneal injection. The average size of tumors in the (+)-JQ1 treatment group (n = 10) and vehicle group (n = 10) were similar at the start of treatment. Animals were followed daily for clinical symptoms. Tumor measurements were assessed by caliper measurements, and volume calculated using the formula Vol = 0.5xLxW2. Statistical significance of tumor volumes was calculated by two-sided Students t-test. Comparative survival analysis was performed using the Log-rank (Mantel-Cox) Test, and data were presented as a Kaplain-Meier plot annotated with a measure of statistical significance (pvalue). All animal studies were approved by the IACUC of the DFCI.

Pharmacokinetic Studies in Mice.[1]
Male CD1 mice (24 – 29 gm) were treated with a single dose of (+)-JQ1 at 5 mg kg-1 for intravenous tail vein injection studies and 10 mg kg-1 for oral gavage studies. Approximately 150 μl of blood were taken from animals by retro-orbital puncture under anesthesia with Isoflurane into EDTA tubes at pre-specified time intervals: 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 5, 8 and 24 hours. Three animals were analyzed per time point. Blood samples were put on ice and centrifuged to obtain plasma samples (2000 x.g, 5 min under 4 °C) within 15 minutes post-sampling. Plasma samples were stored at approximately -70 °C until analysis was performed. Mice were provided free access to food and water throughout the study. Compound was formulated for intravenous injection in 10 % DMSO and 10 % HP-β-CD. Pharmcokinetic studies and pharmacologic assay development was performed at ChemPartner (Shanghai, CHINA). Data were analyzed by J.E.B. using Microsoft Excel and GraphPad Prism 5.02.

Formulations used:
1. Dissolved in 5% dextrose; 50 mg/kg; i.p. injection; Nature. 2010 Dec 23;468(7327):1067-73;
2. Dissolved in 10% DMSO and 90% of a 10% 2-hydroxypropyl-β-cyclodextrin solution; Leukemia. 2017 Oct;31(10):2037-2047.;
3. Dissolved in 1% DMSO+5% Glucose+ddH2O; Cell. 2018 Sep 20;175(1):186-199.e19.;
4. Dissolved in 20% hydroxypropyl-β-cyclodextrin, 5% DMSO, 0.2% Tween-80 in saline; Mol Cancer Ther. 2016 Jun;15(6):1217-26.;
5. Dissolved in 1:1 propylene glycol:water; J Biol Chem. 2016 Nov 4;291(45):23756-23768.;
6. Dissolved in 5% DMSO in 10% 2-hydroxypropyl-β-cyclodextrin solution; Cancer Lett. 2017 Aug 28;402:100-109.
References
[1]. Filippakopoulos P, et al. Selective inhibition of BET bromodomains. Nature. 2010 Dec 23;468(7327):1067-73.
[2]. Sakamaki JI, et al. Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and LysosomalFunction. Mol Cell. 2017 May 18;66(4):517-532.e9.
[3]. Matzuk MM, et al. Small-molecule inhibition of BRDT for male contraception. Cell. 2012 Aug 17;150(4):673-84
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C23H25CLN4O2S
Molecular Weight
456.99
Exact Mass
456.13867
Elemental Analysis
C, 60.45; H, 5.51; Cl, 7.76; N, 12.26; O, 7.00; S, 7.02
CAS #
1268524-70-4
Related CAS #
(R)-(-)-JQ1 Enantiomer;1268524-71-5;JQ-1 (carboxylic acid);202592-23-2
Appearance
White to yellow solid
LogP
4.5
tPSA
97.61
SMILES
O=C(OC(C)(C)C)C[ C@H]1C2=NN=C(C)N2C3=C(C(C)=C(C)S3)C(C4=CC=C(Cl)C=C4)=N1
InChi Key
DNVXATUJJDPFDM-KRWDZBQOSA-N
InChi Code
InChI=1S/C23H25ClN4O2S/c1-12-13(2)31-22-19(12)20(15-7-9-16(24)10-8-15)25-17(11-18(29)30-23(4,5)6)21-27-26-14(3)28(21)22/h7-10,17H,11H2,1-6H3/t17-/m0/s1
Chemical Name
tert-butyl (S)-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
Synonyms
Bromodomain Inhibitor; (+)-JQ 1; (+)-JQ-1; (+)-JQ1;
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 91 mg/mL (199.1 mM)
Water:<1 mg/mL
Ethanol:91 mg/mL (199.1 mM)
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.47 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.5 mg/mL (5.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.


Solubility in Formulation 4: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O:5mg/mL

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1882 mL 10.9412 mL 21.8823 mL
5 mM 0.4376 mL 2.1882 mL 4.3765 mL
10 mM 0.2188 mL 1.0941 mL 2.1882 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • (+)-JQ1

    Leukemia and lymphoma cell lines are broadly sensitive to BET-bromodomain inhibition.2011 Oct 4;108(40):16669-74.

  • (+)-JQ1

    Gene expression profiling of LP-1 and Raji cells treated with active or inactive BET inhibitors.2011 Oct 4;108(40):16669-74.

  • (+)-JQ1

    Small molecule BET-bromodomain inhibition suppressesMYCtranscription.2011 Oct 4;108(40):16669-74.

  • (+)-JQ1

    MYC reconstitution significantly protects cells from BET-mediated effects.2011 Oct 4;108(40):16669-74.

  • (+)-JQ1

    BET-bromodomain inhibition decreases tumor load in vivo.2011 Oct 4;108(40):16669-74.

  • (+)-JQ1

    Integrated genomic rationale for BET bromodomains as therapeutic targets in MM.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

    Inhibition of Myc-dependent transcription by theJQ1BET bromodomain inhibitor.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

    BET inhibition suppressesMYCtranscription in MM.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

    Regulation ofMYCtranscription by BET bromodomains.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

    Anti-myeloma activity ofJQ1in vitro.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

    JQ1induces cell cycle arrest and cellular senescence in MM cells.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

    Translational implications of BET bromodomain inhibition in MM.2011 Sep 16;146(6):904-17.

  • (+)-JQ1

  • (+)-JQ1
  • (+)-JQ1
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