product name I-BET-762
Description: I-BET-762, also known as GSK525762A , is an inhibitor for BET proteins with IC50 of ~35 nM in a cell-free assay, it suppresses the production of proinflammatory proteins by macrophages and blocks acute inflammation, and is highly selective over other bromodomain-containing proteins. GSK525762 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.
References: Nature. 2010 Dec 23;468(7327):1119-23; Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14532-7.
423.9
Formula
C22H22ClN5O2
CAS No.
1260907-17-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 84 mg/mL (198.1 mM)
Water: <1 mg/mL
Ethanol: 42 mg/mL warmed (99.1 mM)
Solubility (In vivo)
Synonyms
GSK525762, GSK525762A
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19419458
| In Vitro |
In vitro activity: I-BET-762 is an inhibitor for BET (bromodomain and extra terminal domain) proteins, BRD2, BRD3 and BRD4, binds to the tandem bromodomains of BET with Kd of 50.5–61.3 nM, displaces a tetra-acetylated H4 peptide prebound to tandem bromodomains of BET with IC50 of 32.5–42.5 nM in FRET analysis. I-BET-762 occupies the acetyl-lysine binding pocket of BET proteins and inhibits binding of BET proteins to acetylated histones, thus disrupts the formation of the chromatin complexes essential for expression of inflammatory genes. I-BET-762 treatment during the first 2 d of differentiation alters CD4+ T-cell cytokine production, up-regulated expression of several antiinflammatory gene products and down-regulated expression of several proinflammatory cytokines. Kinase Assay: Fluorescence resonance energy transfer (FRET) titrations. I-BET is titrated against BRD2 (200 nM), BRD3 (100 nM) and BRD4 (50 nM) in 50 mM HEPES pH7.5, 50 mM NaCl, 0.5 mM CHAPS in the presence of tetra-acetylated Histone H4 peptide (200 nM). After equilibrating for 1 hour, the bromodomain protein : peptide interaction is detected using FRET following the addition of 2nM Europium cryptate labelled streptavidin and 10 nM XL-665-labelled anti-6His antibody in assay buffer containing 0.05% (v/v) BSA and 400 mM KF. Plates are read using an Envision Plate reader (excitation 320 nm, emission 615 nm and 665 nm). Cell Assay: CD4+ T cells are isolated from lymph nodes and spleens of 10- to 12-wk old mice and activated with plate bound anti-CD3 and anti-CD28 antibodies in the presence of indicated cytokines. I-BET-762 compounds is included during the 60–72 h of initial activation. Over the course of 5 d of T-cell culture and expansion, the compounds is diluted 12-fold relative to the starting concentrations. |
|---|---|
| In Vivo | I-BET-762 confers protection against lipopolysaccharide-induced endotoxic shock and bacteria induced sepsisa. Single dose of I-BET applied at 1.5 h after LPS injection cures the mice. Twice-daily injections of I-BET for 2 days protects mice against death caused by sepsis. Limited treatment with I-BET-762 exclusively during early priming inhibited the ability of Th1-differentiated 2D2 T cells to induce neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE). |
| Animal model | Mouse model |
| Formulation & Dosage | Dissolved in 20% beta-cyclodextrin, 2% DMSO in 0.9% saline; 30mg/kg; i.v. injection |
| References | Nature. 2010 Dec 23;468(7327):1119-23; Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14532-7. |
