Description
The bromodomain and extra terminal domain (BET) family of proteins, including BRD2, BRD3, and BRD4, affect inflammatory gene expression by controlling the assembly of histone acetylation-
dependent chromatin complexes. I-
BET762 is a synthetic compound which interacts with BET proteins with high-
affinity (K
d = 32.5-
42.5 nM). It blocks binding of BET proteins with acetylated histones, disrupting the formation of chromatin complexes involved in the expression of specific inflammatory genes in activated macrophages. Through these actions, I-
BET762 provides protection against bacteria-
induced sepsis and lipopolysaccharide-
triggered endotoxic shock.
Uses
GSK 525762A, is a BET Bromodomain Inhibitor, which is now in clinical development. BET bromodomains have emerged as promising drug targets for treatment of cancers, inflammatory diseases, and other medical conditions.
Definition
ChEBI: 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide is a benzodiazepine.
Biochem/physiol Actions
I-BET762 possesses anti-inflammatory property by controlling the pro-inflammatory gene expression. I-BET762 hinders the MYC (proto-oncogene) expression in cellular models. This action of I-BET762 might serve as an effective therapy in treating prostate cancer.
References
1) Nicodeme?et al.?(2010),?Suppression of inflammation by a synthetic histone mimic; Nature?468?1119
2) Mirguet?et al.?(2013),?Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains; J. Med. Chem.,?56?7501
3) Bandukwala?et al.?(2012),?Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors; Proc. Natl. Acad. Sci. USA,?109?14532
4) Delmore?et al.?(2011),?BET Bromodomain as a Therapeutic Strategy to Target c-Myc; Cell?146?904
