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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130269 | GEO | 2019/04/24

REPOSITORIES: GEO

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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

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.

2019-02-04 | GSE118152 | GEO

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

| PRJNA484953 | ENA

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

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

| PRJNA534480 | ENA

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

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

| PRJNA534446 | ENA

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

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

| PRJNA484716 | ENA

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family.

Project description:Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.

| S-EPMC7429977 | biostudies-literature

Selective BET bromodomain inhibition as an antifungal therapeutic strategy.

Project description:Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

| S-EPMC5454392 | biostudies-literature

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

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