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

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

PROVIDER: PRJNA484716 | ENA |

REPOSITORIES: ENA

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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

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

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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)

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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.

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-04-24 | GSE130269 | 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 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 proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia

Project description:Selective inhibition of the second bromodomain of BET family proteins is efficacious in preclinical models of AML

2023-03-24 | GSE147534 | GEO

Discovery and Characterization of Second-Generation BET Bromodomain Inhibitor RG6146

Project description:BET Bromodomain inhibition is an epigenetic therapy that is being assessed as an anti-cancer strategy. Herein, we report the structure and activity of RG6146, a novel second-generation clinical grade BET inhibitor that was derived by optimization of the prototypical tool compound JQ1. We demonstrate that RG6146 elicits potent anti-proliferative and pro-apoptotic effects in multiple pre-clinical models of hematologic malignancies, including multiple myeloma (MM) and B-cell lymphoma. We show that the anti-tumor effects of RG6146 correlated with robust modulation of oncogenic transcription that results in suppression of oncogenic transcription factors, such as MYC, as well as direct activation of the intrinsic apoptotic cascade. Subcutaneous or intraperitoneal administration of RG6146 to tumor-bearing mice was well tolerated and led to pronounced anti-tumor responses in both syngeneic and xenograft tumor models, respectively. Finally, we investigated the ability for RG6146 to augment the activity of other targeted therapies in vitro and in vivo, demonstrating clear combination activity with BCL-2 inhibitor Venetoclax and anti-PD-1/PD-L1 immune checkpoint blockade. Taken together, our data demonstrates the therapeutic potential of novel pan-BET inhibitor RG6146 in the treatment of hematologic malignancies and highlights multiple mechanism-based combination strategies to enhance anti-tumor activity.

2023-05-31 | GSE203004 | GEO

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