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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165025 | GEO | 2021/01/19

REPOSITORIES: GEO

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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.

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BRD2 CUT & RUN in Calu-3 cells

Project description:we performed CUT&RUN to comprehensively map genomic loci bound to BRD2 in control and BRD2 knockdown Calu-3 cells. We also included H2A.Z, H3K4me3 and IgG antibodies.

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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).

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

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

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Mapping genomic loci bound to BRD2 in Calu-3 cells

Project description:we performed CUT&RUN to comprehensively map genomic loci bound to BRD2 in Calu-3 cells. We also included H3K4me3 and IgG antibodies as postive and negative controls, repectively

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BRD2 CUT & RUN in Calu-3 cells

Project description:BRD2 CUT & RUN in Calu-3 cells

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Brd2 regulates gene expression and alternative splicing.

Project description:We analyzed a role of Brd2 protein in transcription and alternative splicing. 289 genes change alternative splicing after Brd2 knockdown and 1459 genes alter gene expression compared to cells treated with negative control siRNA. 6 samples (3 independent samples of cells treated with Brd2 siRNA, 3 samples of cells treated with negative control siRNA)

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

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

2019-10-23 | GSE130247 | 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.

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