Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

Gilan, Omer; Rioja, Inmaculada; Knezevic, Kathy; Bell, Matthew; Yeung, Miriam M.; Harker, Nicola; Lam, Enid Y.N.; Chung, Chun‐wa; Bamborough, Paul; Petretich, Massimo; Urh, Marjeta; Atkinson, Sophie; Bassil, Anna K.; Roberts, Emma J.; Vassiliadis, Dane; Burr, Marian L.; Preston, Alex; Wellaway, Christopher R.; Werner, Thilo; Gray, James R.; Michon, Anne-Marie; Gobbetti, Thomas; Kumar, Vinod; Soden, Peter E.; Haynes, Andrea; Vappiani, Johanna; Tough, David F.; Taylor, S.; Dawson, Sarah‐Jane; Bantscheff, Marcus; Lindon, Matthew; Drewes, Gerard; Demont, Emmanuel H.; Daniels, Danette L.; Grandi, Paola; Prinjha, Rab K.; Dawson, Mark A.

doi:10.1126/science.aaz8455

Cited by 306 publications

(502 citation statements)

References 46 publications

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“…In general this study and various pre-clinical studies published by us and others present a rationale for antifibrotic effects of BET inhibitors and therefore a rationale for further human clinical investigation of this class of agents in CKD [45][46][47]54,55 . Different BET inhibitors, which specifically inhibit either the first (BD1) or the second (BD2) bromodomain of the BET proteins can have different functional contributions to the biological effects of BET inhibitors 56 . BD2 inhibitors were predominantly effective in inflammation-related disorders 56 .…”

Section: Discussionmentioning

confidence: 99%

“…Different BET inhibitors, which specifically inhibit either the first (BD1) or the second (BD2) bromodomain of the BET proteins can have different functional contributions to the biological effects of BET inhibitors 56 . BD2 inhibitors were predominantly effective in inflammation-related disorders 56 . Apabetalone is an example of a BD2 inhibitor used in clinical trials 57 .…”

Section: Discussionmentioning

confidence: 99%

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Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury

Wilflingseder

Willi²,

Lee³

et al. 2020

Nat Commun

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The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can also lead to fibrosis and progressive kidney disease. There is currently limited knowledge about transcriptional regulators regulating these repair programs. Herein we establish the enhancer and superenhancer landscape after AKI by ChIP-seq in uninjured and repairing kidneys on day two after ischemia reperfusion injury (IRI). We identify key transcription factors including HNF4A, GR, STAT3 and STAT5, which show specific binding at enhancer and super-enhancer sites, revealing enhancer dynamics and transcriptional changes during kidney repair. Loss of bromodomain-containing protein 4 function before IRI leads to impaired recovery after AKI and increased mortality. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data also call attention to potential caveats involved in use of BET inhibitors in patients at risk for AKI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury

Wilflingseder

Willi²,

Lee³

et al. 2020

Nat Commun

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“…Likewise, BD-dependent interactions between BRD4 and p65/RelA-K310ac have been implicated in innate immunity 26 and similar interactions with several hematopoietic TFs (including PU.1, FLI1, and ERG) are essential for acute myeloid leukemia pathogenesis 30 . The advent of small molecules with a selectivity for BD1 vs. BD2 have stimulated further interest in dissecting the relative contribution of each of these domains in a variety of cellular contexts 66,67 .…”

Section: Discussionmentioning

confidence: 99%

BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

Padmanabhan

Alexanian

Linares-Saldana

et al. 2020

Preprint

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Gene regulatory networks control tissue plasticity during basal homeostasis and disease in a cell-type specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue-specificity of their function is achieved are poorly understood. BRD4, a member of the BET (Bromo-and Extra-Terminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease, and has been implicated as a pharmacologic target in heart failure.However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. Here, we show that cardiomyocyte-specific deletion of BRD4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature enriched for decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes and preferentially co-localizes with GATA4, a lineage determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. Co-immunoprecipitation assays demonstrate that BRD4 and GATA4 form a complex in a bromodomain-independent manner, revealing a new interaction partner for BRD4 that has functional consequences for target transactivation and may allow for locus and tissue specificity. These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte specific gene program governing bioenergetic homeostasis in the adult heart.

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“…Using the PROTAC approach, BET degraders target BET proteins for ubiquitination and proteasomal destruction ( 71 , 100 ). In addition, compounds have been developed to selectively target one of the two bromodomains (BD1 and BD2) within BET proteins ( 101 , 102 ). BET degraders and selective bromodomain inhibitors both inhibit the growth of prostate cancer cells in vitro and in vivo ( 71 , 100 , 101 ).…”

Section: Bet Proteinsmentioning

confidence: 99%

“…In addition, compounds have been developed to selectively target one of the two bromodomains (BD1 and BD2) within BET proteins ( 101 , 102 ). BET degraders and selective bromodomain inhibitors both inhibit the growth of prostate cancer cells in vitro and in vivo ( 71 , 100 , 101 ). Therefore, ongoing trials, combination treatments and new compounds, may provide opportunities to treat CRPC by targeting BET proteins.…”

Section: Bet Proteinsmentioning

confidence: 99%

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

et al. 2020

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The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.

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Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

Cited by 306 publications

References 46 publications

Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury

Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury

BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

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