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Discovery and Characterization of Second-Generation BET Bromodomain Inhibitor RG6146

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE203004 | GEO | 2023/05/31

REPOSITORIES: GEO

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Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 ÂµM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).

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Discovery and Characterization of Second-Generation BET Bromodomain Inhibitor RG6146

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