Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia

Dawson, Mark A.; Prinjha, Rab K.; Dittmann, Antje; Giotopoulos, George; Bantscheff, Marcus; Chan, Wai-In; Robson, Samuel; Chung, Chun‐wa; Hopf, Carsten; Savitski, Mikhail M.; Huthmacher, Carola; Gudgin, Emma; Lugo, Dave; Beinke, Sören; Chapman, Trevor; Roberts, Emma J.; Soden, Peter E.; Auger, Kurt R.; Mirguet, Olivier; Doehner, Konstanze; Delwel, Ruud; Burnett, Alan Kenneth; Jeffrey, Philip D.; Drewes, Gerard; Lee, Kevin; Huntly, Brian J. P.; Kouzarides, Tony

doi:10.1038/nature10509

Cited by 1,375 publications

(1,347 citation statements)

References 21 publications

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“…A rich literature has been established around the benefits of inhibiting K ac 'erasing' events on chromatin in the past decades in order to affect gene expression, resulting in approved drugs as well as a large number of drug candidates, currently on clinical trials, targeting HDACs in cancer and neurodegenerative diseases such as Parkinson and Alzheimer [14][15][16][17][18]. Recently also proteins that are responsible for the 'readout' of K ac , such as Bromodomains have emerged as potential drug targets and have been successfully targeted by small molecule inhibitors [19][20][21].…”

Section: Lysine Acetylation -A Prominent Post Translation Modificationmentioning

confidence: 99%

“…This acetyl lysine mimetic scaffold has also been further optimized to yield the highly potent and specific BET inhibitor I-BET151 which also showed improved pharmacokinetics when compared to earlier benzodiazepines such as IBET and JQ1, exhibiting good efficacy against human and murine acute leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis [21]. The developed chemical molecules provide excellent tools for proof-of-concept studies in different disease backgrounds.…”

Section: Inhibition Of Brd-specific K Ac Readoutmentioning

confidence: 99%

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The bromodomain interaction module

2012

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a b s t r a c t e-N-acetylation of lysine residues (K ac ) is one of the most abundant post-translation modifications (PTMs) in the human proteome. In the nucleus, acetylation of histones has been linked to transcriptional activation of genes but the functional consequences of most acetylation events and proteins recruited to these sites remains largely unknown. Bromodomains (BRDs) are small helical interaction modules that specifically recognize acetylation sites in proteins. BRDs have recently emerged as interesting targets for the development of specific protein interaction inhibitors, enabling a novel exiting strategy for the development of new therapies. This review provides an overview over sequence requirements of BRDs, known substrates and the structural mechanisms of specific K ac recognition.

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Section: Lysine Acetylation -A Prominent Post Translation Modificationmentioning

confidence: 99%

Section: Inhibition Of Brd-specific K Ac Readoutmentioning

confidence: 99%

The bromodomain interaction module

2012

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“…BRD4 also facilitates transcription elongation. Highly selective BET bromodomain inhibitors, such as JQ-1, 127-129 I-BET151, 130,131 I-BET762, 132 INCB054329, 126 and OTX-015, 133 have been generated to specifically target the recognition of acetylated lysine residues of BETs. Competitive binding with a BET bromodomain inhibitor blocks the binding between BRD4 and acetylated histones, leading to transcriptional inactivation (Fig.…”

Section: Bromodomain and Extraterminalmentioning

confidence: 99%

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Maury

Hashizume

2017

Epigenetics

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Malignancies are characterized by the reprogramming of epigenetic patterns. This reprogramming includes gains or losses in DNA methylation and disruption of normal patterns of covalent histone modifications, which are associated with changes in chromatin remodeling processes. This review will focus on the mechanisms underlying this reprogramming and, specifically, on the role of histone modification in chromatin machinery and the modifications in epigenetic processes occurring in brain cancer, with a specific focus on epigenetic therapies for pediatric brain tumors.

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“…[4][5][6][7][8][9]. The inhibitor JQ1 inhibits the growth of multiple myeloma and AML tumors by downregulating the expression of MYC (6-9).…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Lenhart

Kirov

Desilva

et al. 2015

Molecular Cancer Therapeutics

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The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.

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Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia

Cited by 1,375 publications

References 21 publications

The bromodomain interaction module

The bromodomain interaction module

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

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