RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist

McLure, Kevin G.; Gesner, Emily M.; Tsujikawa, Laura; Kharenko, Olesya A.; Attwell, Sarah; Campeau, Eric; Wasiak, Sylwia; Stein, Adam J.; White, André; Fontano, Eric; Suto, R.K.; Wong, Norman C.W.; Wagner, Glenn; Hansen, Henrik C.; Young, Peter R.

doi:10.1371/journal.pone.0083190

Cited by 171 publications

(177 citation statements)

References 47 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.

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196

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.

Self Cite

196

149

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“…Turning on endogenous production of ApoA-I to facilitate new HDL particle formation is becoming one of the most attractive approaches, which is strongly supported by results from human ApoA-I transgenic mice and virus-mediated overexpression of ApoA-I in a mouse model of experimental atherosclerosis (11,12). RVX-208, a bromodomain and extraterminal domain inhibitor, is an orally active small molecule that upregulates ApoA-I production (12)(13)(14). However, in patients with CHD, administration of RVX-208 did not statistically reduce cardiovascular events and the percentage of coronary atheroma volume due to its small effect on HDL-C levels and significant side effects in the ASSURE study (15,16).…”

Section: Introductionmentioning

confidence: 99%

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Guo¹,

Fan²,

Zhang³

et al. 2015

Journal of Clinical Investigation

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“…BET bromodomain inhibitors (BETi) block this binding, resulting in broad transcriptional changes (12)(13)(14)(15)(16). Recently, we demonstrated that vorinostat triggers transcriptional changes that are overlapping with those induced by BETi in murine Myc-induced lymphoma cells (17).…”

Section: Introductionmentioning

confidence: 99%

Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins

et al. 2016

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Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. Cancer Res; 76(8); 2376-83. Ó2016 AACR.

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RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist

Cited by 171 publications

References 47 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

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins

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