Transcriptional super-enhancers and the BET bromodomain protein BRD4 are emerging as critical drivers of tumorigenesis and therapeutic targets. Characterized by substantial accumulation of histone H3 lysine 27 acetylation (H3K27ac) signals at the loci of cell identity genes and critical oncogenes, super-enhancers are recognized, bound and activated by BRD4, resulting in considerable oncogene over-expression, malignant transformation, cancer cell proliferation, survival, tumor initiation and progression. Small molecule compound BRD4 BD1 and BD2 bromodomain inhibitors block BRD4 binding to super-enhancers, suppress oncogene transcription and expression, reduce cancer cell proliferation and survival, and repress tumor progression in a variety of cancer types. Like other targeted therapy agents, BRD4 inhibitors show moderate anticancer effects on their own, and exert synergistic anticancer effects in vitro and in preclinical models, when combined with other anticancer agents including CDK7 inhibitors, CBP/p300 inhibitors and histone deacetylase inhibitors. More recently, BRD4 BD2 bromodomain selective inhibitors, proteolysis-targeting chimera (PROTAC) BRD4 protein degraders, and dual BRD4 and CBP/p300 bromodomain co-inhibitors have been developed and shown better anticancer efficacy and/or safety profile. Importantly, more than a dozen BRD4 inhibitors have entered clinical trials in patients with cancer of various organ origins. In summary, super-enhancers and their reader BRD4 are critical tumorigenic drivers, and BRD4 BD1 and BD2 bromodomain inhibitors, BRD4 BD2 bromodomain selective inhibitors, PROTAC BRD4 protein degraders, and dual BRD4 and CBP/p300 bromodomain co-inhibitors are promising novel anticancer agents for clinical translation.

转录超级增强子和 BET 溴结构域蛋白 BRD4 正在成为肿瘤发生和治疗靶点的关键驱动因素。其特点是组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 信号在细胞识别基因和关键癌基因位点大量积累，超级增强子被 BRD4 识别、结合和激活，导致大量癌基因过度表达、恶性转化、癌细胞增殖、存活、肿瘤发生和进展。小分子化合物 BRD4 BD1 和 BD2 溴结构域抑制剂可阻断 BRD4 与超级增强子的结合，抑制癌基因转录和表达，减少癌细胞增殖和存活，并抑制多种癌症类型的肿瘤进展。与其他靶向治疗药物一样，BRD4抑制剂本身表现出中等的抗癌作用，并在体外和临床前模型中与其他抗癌药物（包括CDK7抑制剂、CBP/p300抑制剂和组蛋白脱乙酰酶抑制剂）联合使用时发挥协同抗癌作用。最近，BRD4 BD2 溴结构域选择性抑制剂、蛋白水解靶向嵌合体 (PROTAC) BRD4 蛋白降解剂以及 BRD4 和 CBP/p300 溴结构域双抑制剂已被开发出来，并显示出更好的抗癌功效和/或安全性。重要的是，已有十多种 BRD4 抑制剂进入了针对各种器官来源的癌症患者的临床试验。总之，超级增强子及其读取器 BRD4 是关键的致瘤驱动因素，BRD4 BD1 和 BD2 溴结构域抑制剂、BRD4 BD2 溴结构域选择性抑制剂、PROTAC BRD4 蛋白降解剂以及 BRD4 和 CBP/p300 溴结构域双重抑制剂是有前途的新型抗癌药物用于临床翻译。