RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

Picaud, S.; Wells, Christopher; Felletar, I.; Brotherton, Deborah; Martin, Sarah; Savitsky, P.; Díez-Dacal, Beatriz; Philpott, Martin; Bountra, C.; Lingard, Hannah; Fedorov, Oleg; Müller, Susanne; Brennan, P.E.; Knapp, Stefan; Filippakopoulos, P.

doi:10.1073/pnas.1310658110

Cited by 412 publications

(435 citation statements)

References 45 publications

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“…RVX2135 belongs to a different scaffold, which has a higher selectivity for BD2 over BD1 of the BET proteins. This property is shared by RVX-208, a BET inhibitor with the same scaffold that is undergoing clinical trial for arteriosclerosis (13)(14)(15). Nevertheless, despite the BD2 selectivity, RVX2135 blocks cell-cycle progression and induces cell death in Myc-induced mouse lymphoma cells in vitro and in mice (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…RVX2135 is a novel small-molecule BET bromodomain inhibitor that is structurally unrelated to the benzodiazepine derivative compounds but is in the same chemical scaffold group as RVX-208 developed by Zenith Epigenetics Corp. (Fig. 1A) (13)(14)(15). In a fluorescence resonance energy transfer assay in vitro, RVX2135 and the prototype BET inhibitor JQ1 displaced all four BET family members from tetraacetylated histone peptide (Brd2, Brd3, Brd4, and BrdT) with low or submicromolar potency ( Fig.…”

Section: Rvx2135 Blocks Proliferation Of Myc-induced Mouse Lymphoma Cmentioning

confidence: 99%

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BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury

Nilsson

Muralidharan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

199

149

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The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myctransgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.T he bromodomain and extraterminal (BET) domain family of proteins Brd2, Brd3, Brd4, and BrdT bind via their tandem bromodomains (BD1 and BD2) to acetylated lysines in histones and other proteins (1). On binding, they regulate the transcription of genes critical for cell-cycle progression and apoptosis. Therefore, BET proteins have emerged as interesting proteins for targeted intervention of cancer.Recently, the small-molecule BET inhibitor (+)-JQ-1 (hereafter JQ1) was found to be a potent and specific suppressor of B cell-lineage malignancies (2, 3). In acute myelogenous leukemia, BRD4 is essential for tumor maintenance, and JQ1 recapitulates the effects of RNA interference of BRD4 (4, 5). JQ1 was subsequently shown to have an antiproliferative effect in other hematological malignancies and solid organ tumors including glioblastoma, prostate cancer, and neuroblastoma (6-10). The current model of how BET inhibitors (BETi) inhibit tumor cell proliferation places inhibition of MYC as mediating activity in lymphoid tumors, with Myc-independent activity in some solid tumor types such as lung adenocarcinoma (11). However, it has not been clear in hematopoietic tumor types whether the antiproliferative effects of BETi are mediated by suppression of MYC expression or whether effects on MYC are a correlative bystander of the mechanism, perhaps useful as a biomarker but not necessarily mechanistic (12).We have assessed the effect of RVX2135, a novel and orally bioavailable selective inhibitor of Brd2, Brd3, Brd4, and BrdT, in in vitro and in vivo models of Myc-induced lymphoma. We find that the effects are mediated by broad transcriptional changes and that these are genetically and functionally linked to histone deacetylase inhibitors. Results RVX2135 Blocks Proliferation of Myc-Induced Mouse Lymphoma Cellsand Induces Caspase-Dependent Apoptosis. RVX2135 is a novel small-molecule BET bromodoma...

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Section: Discussionmentioning

confidence: 99%

Section: Rvx2135 Blocks Proliferation Of Myc-induced Mouse Lymphoma Cmentioning

confidence: 99%

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury

Nilsson

Muralidharan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

199

149

View full text Add to dashboard Cite

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“…To test if our definition of regulatory potential could predict BET-inhibitor repressed genes, we examined five diffuse large Bcell lymphoma (DLBCL) cell lines (Chapuy et al 2013), one liver cancer cell line (HepG2) (Picaud et al 2013) and one malignant peripheral nerve sheath tumor cell line (90-8TL) (De Raedt et al 2014) in which BET-inhibitor effects were measured using expression microarrays and H3K27ac ChIP-seq (Chapuy et al 2013;Picaud et al 2013;De Raedt et al 2014). Using H3K27ac ChIP- Figure 1.…”

Section: H3k27ac Defined Regulatory Potentials Identify Genes Suppresmentioning

confidence: 99%

Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles

et al. 2016

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Model-based analysis of regulation of gene expression (MARGE) is a framework for interpreting the relationship between the H3K27ac chromatin environment and differentially expressed gene sets. The framework has three main functions: MARGE-potential, MARGE-express, and MARGE-cistrome. MARGE-potential defines a regulatory potential (RP) for each gene as the sum of H3K27ac ChIP-seq signals weighted by a function of genomic distance from the transcription start site. The MARGE framework includes a compendium of RPs derived from 365 human and 267 mouse H3K27ac ChIP-seq data sets. Relative RPs, scaled using this compendium, are superior to superenhancers in predicting BET (bromodomain and extraterminal domain) -inhibitor repressed genes. MARGE-express, which uses logistic regression to retrieve relevant H3K27ac profiles from the compendium to accurately model a query set of differentially expressed genes, was tested on 671 diverse gene sets from MSigDB. MARGE-cistrome adopts a novel semisupervised learning approach to identify cis-regulatory elements regulating a gene set. MARGE-cistrome exploits information from H3K27ac signal at DNase I hypersensitive sites identified from published human and mouse DNase-seq data. We tested the framework on newly generated RNA-seq and H3K27ac ChIP-seq profiles upon siRNA silencing of multiple transcriptional and epigenetic regulators in a prostate cancer cell line, LNCaP-abl. MARGE-cistrome can predict the binding sites of silenced transcription factors without matched H3K27ac ChIP-seq data. Even when the matching H3K27ac ChIP-seq profiles are available, MARGE leverages public H3K27ac profiles to enhance these data. This study demonstrates the advantage of integrating a large compendium of historical epigenetic data for genomic studies of transcriptional regulation.

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“…Studies have shown that BD selective BETis modify different transcriptional outcomes compared with non-selective BETis (Picaud et al, 2013;Gacias et al, 2014), implying that BD selectivity may have differential biological consequences that impact inflammation. RVX-297 is a novel, orally bioavailable BETi that has a 47-to 58-fold greater affinity for BD2 than for BD1 in the BET family of proteins (Kharenko et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Jahagirdar

Attwell²,

Marušić³

et al. 2017

Mol Pharmacol

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Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.

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RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

Cited by 412 publications

References 45 publications

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

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