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

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. mRNA profiles of 22RV1 cells treated with ABBV-075, ABBV-744, or Enzalutmide in the presence or absence of DHT were generated by deep sequencing, in duplicate, using Illumina HiSeq3000.

本研究报道了ABBV-744的发现——这是一款同类首创、强效且高选择性的BET家族BD2结构域抑制剂，具备类药成药性。RNA测序（RNA-seq）分析结果显示，ABBV-744可强效抑制雄激素受体（Androgen Receptor, AR）依赖的转录过程，且不会引发泛BET抑制剂暴露后所伴随的广泛转录组改变。本研究采用Illumina HiSeq3000测序平台，对经ABBV-075、ABBV-744或恩扎卢胺（Enzalutmide）处理，且分别在存在或不存在双氢睾酮（Dihydrotestosterone, DHT）条件下培养的22RV1细胞，以双重复方式开展深度测序，从而获取其mRNA表达谱。