Discovery and Characterization of Second-Generation BET Bromodomain Inhibitor RG6146

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. Using RNA-sequencing (RNA-seq) to examine changes in gene expression of Eµ-Myc cells treated in triplicate with BET Bromodomain inhibitors, JQ1 or RG6146, or DMSO vehicle control.