From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151

Mirguet, Olivier; Lamotte, Yann; Donche, Frédéric; Toum, Jérôme; Gellibert, Françoise; Bouillot, Anne; Gosmini, Romain; Nguyen, Van-Loc; Delannée, Delphine; Seal, Jonathan; Blandel, Florence; Boullay, Anne-Bénédicte; Boursier, Eric; Martin, Sandrine; Brusq, Jean-Marie; Krysa, Gaël; Riou, Alizon M.; Tellier, Rémi; Costaz, Agnès; Huet, Pascal; Dudit, Yann; Trottet, Lionel; Kirilovsky, Jorge; Nicodème, Edwige

doi:10.1016/j.bmcl.2012.01.125

Cited by 112 publications

(116 citation statements)

References 11 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…10). In addition, prompted by this, several structure/ activity-based BET protein small-molecule inhibitors have been developed, including JQ1 and I-BET151 (IB), which displace the BET proteins, along with the associated transcript initiation and elongation factors, from the chromatin (11)(12)(13). This results in transcriptional repression of BCL2, c-MYC, and CDK6 as well as induces growth arrest and apoptosis of AML cells (14,15).…”

Section: Introductionmentioning

confidence: 99%

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

172

170

View full text Add to dashboard Cite

The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1cþ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34 þ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142-54. Ó2014 AACR.

show abstract

Section: Introductionmentioning

confidence: 99%

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

172

170

View full text Add to dashboard Cite

show abstract

“…N-((2S*,4R*)-1-Acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (58a) was reacted with morpholine using method E. After formamide deprotection using method A, coupling of phenylboronic acid was carried out using method B; mp 80°C. LCMS (method formate): retention time 1.18 min, [M + H] ((2S*,4R*)-2-Methyl-4-(phenylamino)-6-(3-(piperidin-1-ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(24). Suzuki coupling between N-((2S*,4R*)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (54) and (3-formylphenyl)boronic acid was carried out using method C. The resulting aldehyde was coupled with piperidine using method E. After formamide deprotection using method A, phenylboronic acid was coupled using method B. LCMS (method formate)dihydroquinolin-1(2H)-yl)ethanone(27).…”

mentioning

confidence: 99%

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

et al. 2014

Self Cite

View full text Add to dashboard Cite

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

show abstract

“…Increasing ApoA1 levels has emerged as a promising approach for the treatment of atherosclerosis (30), and recent phase IIb clinical trial data using RVX-208 as an ApoA1 modulator have been encouraging (28). ApoA1 expression is regulated by BET proteins, and chemical inhibition of BET bromodomains has been associated with ApoA1 up-regulation on transcriptional and protein levels (9,31,32). As a consequence, a similar mode of action has also been suggested for RVX-208, but no data characterizing the RVX-208/BET interaction have been published so far.…”

mentioning

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.

412

406

View full text Add to dashboard Cite

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

show abstract

From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151

Cited by 112 publications

References 11 publications

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

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

Contact Info

Product

Resources

About