PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains

Picaud, S.; Costa, David da; Thanasopoulou, Angeliki; Filippakopoulos, P.; Fish, Paul V.; Philpott, Martin; Fedorov, O.; Brennan, P.E.; Bunnage, Mark E.; Owen, Dafydd R.; Bradner, James E.; Taniere, Phillippe; O’Sullivan, B.; Müller, Susanne; Schwaller, Juerg; Stankovic, Tatjana; Knapp, Stefan

doi:10.1158/0008-5472.can-12-3292

Cited by 218 publications

(206 citation statements)

References 45 publications

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“…The in vivo data presented here and previous studies using other BETi have shown that inhibition of BET proteins is tolerated in mice (3,18,44,45). BETi exhibit broad transcriptional effects by targeting the general transcriptional elongation factor p-TEFb's interplay with Brd4.…”

Section: Discussionmentioning

confidence: 53%

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.

198

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: 53%

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.

198

149

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“…In accordance with the cell-cycle arrest observed at 24 to 48 hours, E2F1 target genes, but not E2F1 itself, are downregulated by both OTX015 and JQ1 (10), at a later time point than the effect on MYC or on TLR/JAK/STAT pathways. The high synergism reported in leukemia preclinical models with the combination of the BET bromodomain inhibitor PFI-1 with a pan-aurora kinase inhibitor (12) suggests that the combination of BET bromodomain inhibitors with drugs targeting the cell cycle might overcome the observed lower sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…8). Furthermore, BET bromodomain inhibitors have shown antitumor activity in different preclinical models derived from hematologic or solid tumors (4,5,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The compounds induce cell-cycle arrest in G 1 and, depending on the type of tumor model, apoptosis or cell differentiation (4,5,9,11,21).…”

Section: Introductionmentioning

confidence: 99%

The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Boi

Gaudio

Bonetti

et al. 2015

Clinical Cancer Research

247

297

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Purpose: In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015.Experimental Design: We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound.Results: OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC 50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC-and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11.Conclusions: Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.

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“…Exposure of these cells to the potent pan-BET inhibitor PFI-1 (10, 35) led to significant reduction of recovery times of the photobleached nuclear region, suggesting efficient dissociation of BRD3 from chromatin ( Fig. 3), even at concentrations as low as 100 nM, given that the in vitro dissociation constant for this inhibitor is 80 nM for the BD1 of BRD3 and 76 nM for BD2 (35). At 250 nM, recovery times reached a plateau that did not decrease further at higher concentrations of the inhibitor.…”

Section: Rvx-208 Presents a Template For Bd2 Rearrangement Upon Bindingmentioning

confidence: 99%

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

Picaud

Wells

Felletar

et al. 2013

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

Self Cite

406

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Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.small molecule inhibitor | epigenetics | microarray | ApoA1

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PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains

Cited by 218 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

The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

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

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