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I-BET-762

Cat. No. M2190
I-BET-762 Structure
Synonym:

GSK525762

Size Price Availability Quantity
5mg USD 90 In stock
10mg USD 135 In stock
50mg USD 450 In stock
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Quality Control
Biological Activity

I-BET-762 (GSK525762) is a small molecule inhibitor of the BET (Bromodomain and Extra-Terminal) family of bromodomain-containing proteins. BET inhibitor I-BET-762 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. I-BET-762 (GSK525762) was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Treatment of naive CD4(+) T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells.

Protocol
Cell Experiment
Cell lines isolated CD4+ T cells
Preparation method CD4+ T cells are isolated from lymph nodes and spleens of 10- to 12-wk-old 2D2 transgenic mice by using Invitrogen Dynal Beads according to manufacturer’s protocols. The isolated CD4+ T cells were stimulated with platebound anti-CD3 and anti-CD28 antibodies alone (ThN conditions), or in the presence of anti-IL4 and IL-12 (Th1 conditions), IL-4 and anti-IL12 (Th2 conditions), IL-1β, IL-6, and IL-23 (Th17 conditions), or TGF-β (Treg conditions). Along with the cytokine mixtures were included either the Control-768 (GSK525768A) or I-BET-762 (GSK525762A) compounds. The cells are stimulated in these condition for 60–72 h and then harvested and expanded with DMEM media containing 10% (vol/vol) FBS, antibiotics, Lglutamine, and B-2ME. The cells were counted and reset to 0.5 × 106 cells per mL on days 3 and 4 after initial stimulation. Over the course of 5 d of T-cell culture and expansion, the compounds were diluted 12-fold relative to the starting concentrations. In case of Th1, Th2, and iTreg conditions, IL-2 was added to the media at a final concentration of 20 units per mL. On day 5 after initial activation, the cells were harvested and restimulated with PMA (10 nM) and ionomycin (1 μM) for 6 h. Brefeldin A (10 μg/mL) was added during the last 2 h of stimulation. Subsequently, the cells were fixed with 4% (wt/vol) paraformaldehyde in PBS for 15 min at 25 °C, washed in PBS, and permeabilized in saponin buffer [PBS, 0.5% saponin (Sigma), 1% (wt/vol) BSA, and 0.1% (wt/vol) sodium azide]. Intracellular staining was performed as described for indicated cytokines. In some experiments, cell surface staining was completed before fixation.
Concentrations 125, 250, 500nM
Incubation time 60-72h
Animal Experiment
Animal models LPS-induced endotoxic shock of C57BL/6 mice model
Formulation 20% beta-cyclodextrin, 2% DMSO in 0.9% saline
Dosages 30 mg/kg
Administration retro-orbital or tail vein injection
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 423.9
Formula C22H22ClN5O2
CAS Number 1260907-17-2
Purity >99%
Solubility DMSO
Storage at -20°C
References

Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors.
Bandukwala HS, et al. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14532-7. PMID: 22912406.

BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
Delmore JE, et al. Cell. 2011 Sep 16;146(6):904-17. PMID: 21889194.

Suppression of inflammation by a synthetic histone mimic.
Nicodeme E, et al. Nature. 2010 Dec 23;468(7327):1119-23. PMID: 21068722.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: I-BET-762, GSK525762 supplier, Epigenetic Reader Domain, inhibitors

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