Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
Pharmacol Ther. 2023 Mar;243:108354. doi: 10.1016/j.pharmthera.2023.108354. Epub 2023 Feb 3.
Bromodomain and extra-terminal (BET) family member proteins (BRD2, BRD3, BRD4 and BRDT) play a pivotal role in interpreting the epigenetic information of histone Kac modification, thus controlling gene expression, remodeling chromatin structures and avoid replicative stress-induced DNA damages. Abnormal activation of BET proteins is tightly correlated to various human diseases, including cancer. Therefore, BET bromodomain inhibitors (BBIs) were considered as promising therapeutics to treat BET-related diseases, raising >70 clinical trials in the past decades. Despite preliminary effects achieved, drug resistance and adverse events represent two major challenges for current BBIs development. In this review, we will introduce the biological functions of BET proteins in both physiological and pathological conditions; and summarize the progress in current BBI drug development. Moreover, we will also discuss the major challenges in the front of BET inhibitor development and provide rational strategies to overcome these obstacles.
溴结构域和末端（BET）家族成员蛋白（BRD2、BRD3、BRD4 和 BRDT）在解释组蛋白 Kac 修饰的表观遗传信息方面发挥着关键作用，从而控制基因表达、重塑染色质结构和避免复制应激诱导的 DNA 损伤。BET 蛋白的异常激活与多种人类疾病密切相关，包括癌症。因此，BET 溴结构域抑制剂（BBIs）被认为是治疗 BET 相关疾病的有前途的治疗方法，在过去几十年中引发了超过 70 项临床试验。尽管取得了初步效果，但耐药性和不良反应是当前 BBIs 开发面临的两大挑战。在这篇综述中，我们将介绍 BET 蛋白在生理和病理条件下的生物学功能；并总结当前 BBI 药物开发的进展。此外，我们还将讨论 BET 抑制剂开发面临的主要挑战，并提供克服这些障碍的合理策略。
