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BET inhibitor

About: BET inhibitor is a research topic. Over the lifetime, 427 publications have been published within this topic receiving 25777 citations. The topic is also known as: BET inhibitors & Bromo- and extra-terminal domain inhibitor.


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Journal ArticleDOI
23 Dec 2010-Nature
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

3,489 citations

Journal ArticleDOI
11 Apr 2013-Cell
TL;DR: This work investigates how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition ofThe MYC oncogene in multiple myeloma (MM), and finds that super-enhancers were found at key oncogenic drivers in many other tumor cells.

2,292 citations

Journal ArticleDOI
23 Dec 2010-Nature
TL;DR: A synthetic compound (I-BET) is described that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis.
Abstract: Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

1,407 citations

Journal ArticleDOI
27 Oct 2011-Nature
TL;DR: It is shown that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis, establishing the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
Abstract: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin ‘adaptor’ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.

1,388 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202391
202241
202153
202068
201957
201865