The Bromo- and Extra-Terminal domain (BET) family proteins act as “readers” of acetylated histones and they are important transcription regulators. BRD2, BRD3, BRD4 and BRDT, part of the BET family, are important in different tumors, where upregulation or translocation often occurs. The potential of targeting BET proteins as anti-cancer treatment originated with data obtained with a first series of compounds, and there are now several data supporting BET inhibition in both solid tumors and hematological malignancies. Despite very positive preclinical data in different tumor types, the clinical results have been so far moderate. Using lymphoma as an example to review the data produced in the laboratory and in the context of the early clinical trials, we discuss the modalities to make BET targeting more efficient both generating novel generation of compounds and by exploring the combination with small molecules affecting various signaling pathways, BCL2, or DNA damage response signaling, but also with additional epigenetic agents and with immunotherapy. We also discuss the mechanisms of resistance and the toxicity profiles so far reported.

溴和末端结构域 (BET) 家族蛋白充当乙酰化组蛋白的“阅读器”，它们是重要的转录调节因子。BRD2、BRD3、BRD4 和 BRDT 是 BET 家族的一部分，在不同的肿瘤中很重要，这些肿瘤经常发生上调或易位。靶向 BET 蛋白作为抗癌治疗的潜力源于第一批化合物获得的数据，现在有几项数据支持实体瘤和血液系统恶性肿瘤中的 BET 抑制。尽管在不同的肿瘤类型中获得了非常积极的临床前数据，但迄今为止的临床结果是中等的。以淋巴瘤为例，回顾实验室和早期临床试验中产生的数据，我们讨论了使 BET 靶向更有效的方式，既可以产生新一代化合物，也可以探索与影响各种信号通路、BCL2 或 DNA 损伤反应信号的小分子的组合，以及与其他表观遗传试剂和免疫疗法的组合。我们还讨论了迄今为止报道的耐药机制和毒性特征。