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Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cell line

ABSTRACT: We comprehensively analyzed the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) underlying the antitumor functions of BET inhibitors of human HCC cells using RNA sequencing (RNA-Seq). The pan-BET inhibitor ABBV-075 and BD2 specific inhibitor ABBV-744 attenuates the IFNγ-induced inflammatory response. In addition, BD2 inhibitors were predominantly effective in inflammatory response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189376 | GEO | 2022/05/04

REPOSITORIES: GEO

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Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia

Project description:Dual bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4 and BRDt only displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of GI toxicity, have presented as dose limiting adverse events that may prevented escalation to higher dose levels for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain (BD2) of the four BET family proteins. In contrast to the broad antiproliferative activities observed with DbBi, ABBV-744 displayed significant antiproliferative activities largely but not exclusively in cancer cell lines derived from AML and androgen receptor (AR) positive prostate cancer. Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the Bcl-2 inhibitor, venetoclax (ABT-199) compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).

2021-01-31 | GSE144326 | GEO

Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability (22RV1 RNA-seq)

Project description:Here we report the discovery of ABBV-744, a first in class, highly potent and selective inhibitor of BET family BD2 domains with drug like properties. RNA-seq analysis revealed that ABBV-744 elicited potent inhibition of AR-dependent transcription without causing broad transcription alterations associated with exposure to pan BET inhibitors.

2019-10-23 | GSE130247 | GEO

Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability (LNCaP RNA-seq)

2019-02-04 | GSE118152 | GEO

Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability

Project description:Here we report the discovery of ABBV-744, a first in class, highly potent and selective inhibitor of BET family BD2 domains with drug like properties. ChIP-seq analysis revealed that ABBV-744 displaced BRD4 from AR-containing super enhancers and elicited potent inhibition of AR-dependent transcription without causing broad transcription alterations associated with exposure to pan BET inhibitors.

2020-01-22 | GSE118247 | GEO

Contribution of BET proteins to androgen (DHT)-stimulated gene expression program

Project description:Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and heme malignancies. BET family member BRD4 function at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here we tested the hypothesis that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Further, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene regulatory regions co-occupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of eRNA transcription. ABBV-075 displayed potent anti-proliferative activity in multiple models of resistance to second generation anti-androgens and inhibited the activity of AR-V7 and the AR LBD gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC.

2017-02-21 | GSE86245 | GEO

Identification of potential ABBV-075 responsive markers in human PBMCs

Project description:To identify genes that are modulated by BET inhibitors in blood, we determined global gene expression changes in ABBV-075-treated human PBMC samples

2017-03-07 | GSE89933 | GEO

Identification of potential ABBV-075 responsive markers in mouse whole blood

Project description:To identify genes that are modulated by BET inhibitors in blood, we determined global gene expression changes in ABBV-075-treated mouse whole blood samples

2017-03-07 | GSE89935 | GEO

BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2

Project description:We performed RNA sequencing of Calu-3 cells after treatment with the BET-domain inhibitors JQ-1 and ABBV-744 as well as BRD2 CRISPRi knockdown. We also included CRISPRi knockdown of two other validated hit genes from our screen, COMP and ACE2.

2021-01-19 | GSE165025 | GEO

Brd2 inhibitor ABBV-744 inhibits SARS-CoV-2 infection in Syrian Hamsters

Project description:We tested if Brd2 inhibitor ABBV-744 could reduce SARS-CoV-2 infection in Syrian Hamsters. Three days post-infection, the lungs of hamsters were harvested and subjected to RNA-seq. Infected, but untreated, hamsters showed marked up-regulation of a number of genes including ISGs when compared to uninfected controls. In contrast, hamsters treated with ABBV-744 showed a down-regulation of ISG levels, confirming ABBV-744 activity. Thus, Brd2 inhibition can decrease SARS-CoV-2 infection in Syrian Hamsters.

2021-09-02 | GSE182994 | GEO

Effect of EZH2 and BET bromodomain inhibition, alone and combined, on NUT carcinoma gene expression

Project description:To determine mechanisms of synergy between EZH2 and BRD4-NUT, we treated NUT carcinoma cell lines with EZH2 inhibitor, tazemetostat, and/or BET bromodomain inhibitors (ABBV075 pan-BET inhibitor or ABBV744 BD2-selective inhibitor). We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different NUT carcinoma cell lines at two time points, 6h and 96h.

2023-10-05 | GSE208774 | GEO

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