Clinical progress and pharmacology of small molecule bromodomain inhibitors

Theodoulou, Natalie H.; Tomkinson, Nicholas C. O.; Prinjha, Rab K.; Humphreys, P. G.

doi:10.1016/j.cbpa.2016.05.028

Cited by 71 publications

(67 citation statements)

References 48 publications

(43 reference statements)

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“…Bromodomain-mediated interactions have key roles in transcriptional regulation and their dysfunction is implicated in a large number of diseases including cancer [183–185], atherosclerosis [186] and diabetes [187]. …”

Section: Histone Acetyltransferase (Hat) Assaysmentioning

confidence: 99%

Epigenetic assays for chemical biology and drug discovery

Gul

2017

Clin Epigenet

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The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects. The current clinical trials involving the next generation of epigenetic drugs may address the disadvantages of the currently approved epigenetic drugs.The identification of chemical starting points of many drugs often makes use of screening in vitro assays against libraries of synthetic or natural products. These assays can be biochemical (using purified protein) or cell-based (using for example, genetically modified, cancer cell lines or primary cells) and performed in microtiter plates, thus enabling a large number of samples to be tested. A considerable number of such assays are available to monitor epigenetic target activity, and this review provides an overview of drug discovery and chemical biology and describes assays that monitor activities of histone deacetylase, lysine-specific demethylase, histone methyltransferase, histone acetyltransferase and bromodomain. It is of critical importance that an appropriate assay is developed and comprehensively validated for a given drug target prior to screening in order to improve the probability of the compound progressing in the drug discovery value chain.

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Section: Histone Acetyltransferase (Hat) Assaysmentioning

confidence: 99%

Epigenetic assays for chemical biology and drug discovery

Gul

2017

Clin Epigenet

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“…In the context of fibrosis, inhibiting BRD4 with JQ1 inhibits both lung and liver fibrosis as well as HSC activation in murine models, including reducing TGF-β-mediated Col1A1 expression and extracellular matrix remodeling (Tang et al, 2013; Ding et al, 2015). Thus, JQ1 represents an attractive small molecule for further study as potential treatment of human fibroproliferative diseases and the future development of more specific and stable BRD4 inhibitors (Theodoulou et al, 2016; Waring et al, 2016) may open new opportunities for anti-fibrotic therapy.…”

Section: Targeting Matrix Stiffness-induced Gene Expression To Treat mentioning

confidence: 99%

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

et al. 2016

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Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation. Despite the significant progress in our understanding of liver fibrosis, the molecular mechanisms through which the extracellular matrix promotes HSC activation are not well understood and no effective therapies have been approved to date that can target this early, reversible, stage in liver fibrosis. Several new lines of investigation now provide important insight into this area of study and identify two nuclear targets whose inhibition has the potential of reversing liver fibrosis by interfering with HSC activation: Yes-associated protein (YAP), a transcriptional co-activator and effector of the mechanosensitive Hippo pathway, and bromodomain-containing protein 4 (BRD4), an epigenetic regulator of gene expression. YAP and BRD4 activity is induced in response to mechanical stimulation of HSCs and each protein independently controls waves of early gene expression necessary for HSC activation. Significantly, inhibition of either protein can revert the chronic activation of HSCs and impede pathological progression of liver fibrosis in clinically relevant model systems. In this review we will discuss the roles of these nuclear co-activators in HSC activation, their mechanism of action in the fibrotic process in the liver and other organs, and the potential of targeting their activity with small molecule drugs for fibrosis reversal.

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“…2−4 BDs are potentially amenable to small molecule inhibition, as impressively shown in the case of bromo and extra-terminal (BET) BD inhibitors which have been extensively used in recent years to understand the role of this family in normal physiology and pathology, ultimately paving the way for their clinical evaluation in cancer indications. 3−6 In the wake of this success, several other BDs have been successfully targeted by inhibitors with very different scaffolds, further highlighting the druggability of this target family. 7−14 …”

Section: Introductionmentioning

confidence: 99%

Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

et al. 2017

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Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure–activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2– or TAF1–histone H3.3 or H4 interaction assay.

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Clinical progress and pharmacology of small molecule bromodomain inhibitors

Cited by 71 publications

References 48 publications

Epigenetic assays for chemical biology and drug discovery

Epigenetic assays for chemical biology and drug discovery

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

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