Achieving clinical success with BET inhibitors as anti-cancer agents

Shorstova, Tatiana; Foulkes, William D.; Witcher, Michael

doi:10.1038/s41416-021-01321-0

Cited by 262 publications

(245 citation statements)

References 133 publications

(224 reference statements)

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Section: Trends In Molecular Medicinementioning

confidence: 99%

“…Currently, BET inhibitors are mostly studied as an anticancer treatment (i.e., 35 out of 45 clinical trials, see Table S1 in the supplemental information online; reviewed in detail [66]). The role of BRD3 and BRD4 in cancer was first described in nuclear protein of testis (NUT) carcinoma, where a translocation causes BRD4 to fuse to NUT, driving cancer development [66,67]. It was then shown that BET inhibition can affect enhancer-driven oncogene expression in cancer cell lines [68] and one BET inhibitor passed Phase I in a clinical trial to treat NUT carcinoma (NCT01987362 i [69]).…”

Section: Trends In Molecular Medicinementioning

confidence: 99%

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Enhancers in disease: molecular basis and emerging treatment strategies

Claringbould

Zaugg

2021

Trends in Molecular Medicine

120

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Enhancers are genomic sequences that play a key role in regulating tissue-specific gene expression levels. An increasing number of diseases are linked to impaired enhancer function through chromosomal rearrangement, genetic variation within enhancers, or epigenetic modulation. Here, we review how these enhancer disruptions have recently been implicated in congenital disorders, cancers, and common complex diseases and address the implications for diagnosis and treatment. Although further fundamental research into enhancer function, target genes, and context is required, enhancer-targeting drugs and gene editing approaches show great therapeutic promise for a range of diseases. HighlightsEnhancer disruption is increasingly implicated as a disease-driving mechanism. Chromosomal rearrangements can cause an enhancer to drive aberrant gene expression, genetic variants in enhancers can impact a transcription factor binding site, and disease-associated epigenetic changes are enriched in enhancer regions.The three big challenges in enhancer research focus on systematically identifying functional enhancers, their target genes, and the context in which they are active.Bromo-and extra-terminal (BET) inhibitors are a new class of drugs that target enhancers and inhibit gene expression. They are under investigation as treatment for cancer and other diseases.Gene editing techniques elucidate enhancer function and are being used to selectively regulate or mutate disturbed enhancers.

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Section: Trends In Molecular Medicinementioning

confidence: 99%

Section: Trends In Molecular Medicinementioning

confidence: 99%

Enhancers in disease: molecular basis and emerging treatment strategies

Claringbould

Zaugg

2021

Trends in Molecular Medicine

120

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“…This feature tightly links BET proteins to cancer. Either in classical NUT fusions as independently of NUT, de-regulation of BET expression accounts for many types of cancer [reviewed in (Shorstova et al, 2021)]. This motivated the development of drugs efficiently detaching BET proteins from chromatin as therapeutic molecules to treat cancer (Filippakopoulos et al, 2010;Dawson et al, 2011;Delmore et al, 2011;Mertz et al, 2011;Zuber et al, 2011), but at the same time they proved also to be effective in suppressing inflammation (Nicodeme et al, 2010).…”

Section: Bet Proteinsmentioning

confidence: 99%

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

García-Gutiérrez

García-Domínguez

2021

Front. Mol. Biosci.

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Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

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“…Confident in our ability to access almost any Ir-drug conjugate, we initiated our target ID campaign with the validated epigenetic tool compound (+)-JQ1 28 . A potent inhibitor of the BET family of bromodomain proteins (BRD2/3/4), several JQ1 structural analogues are in clinical trials for a variety of cancers including NUT midline carcinoma 29 . We prepared the corresponding (+)-JQ1-G2 conjugate (1) (Scheme 2) and validated target engagement in vitro with recombinant BRD4 in a competition assay vs. bovine carbonic anhydrase (CA).…”

Section: Main Textmentioning

confidence: 99%

Small molecule photocatalysis enables drug target identification via energy transfer

Trowbridge

Seath

Rodriguez‐Rivera

et al. 2021

Preprint

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The identification of cellular targets that can be exploited for therapeutic benefit, broadly known as target ID, remains a fundamental goal in drug discovery. In recent years, the application of new chemical and biological technologies that accelerate target ID has become commonplace within drug discovery programs, as a complete understanding of how molecules react in a cellular environment can lead to increased binding selectivity, improved safety profiles, and clinical efficacy. Established approaches using photoaffinity labelling (PAL) are often costly and time-consuming due to poor signal-to-noise coupled with extensive probe optimization. Such challenges are exacerbated when dealing with low abundance membrane proteins or multiple protein target engagement, typically rendering target ID unfeasible. Herein, we describe a general platform for photocatalytic small molecule target ID, which hinges upon the generation of high-energy carbene intermediates via visible light-mediated Dexter energy transfer. By decoupling the reactive warhead from the drug, catalytic signal amplification results in multiple labelling events per drug, leading to unprecedented levels of target enrichment. Through the development of cell permeable photocatalyst conjugates, this method has enabled the quantitative target and off target identification of several drugs including (+)-JQ1, paclitaxel, and dasatinib. Moreover, this methodology has led to the target ID of two GPCRs, ADORA2A and GPR40m, a class of drug target seldom successfully uncovered in small molecule PAL campaigns.

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Achieving clinical success with BET inhibitors as anti-cancer agents

Cited by 262 publications

References 133 publications

Enhancers in disease: molecular basis and emerging treatment strategies

Enhancers in disease: molecular basis and emerging treatment strategies

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

Small molecule photocatalysis enables drug target identification via energy transfer

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