Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, United States.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, United States.
Curr Opin Chem Biol. 2023 Aug;75:102323. doi: 10.1016/j.cbpa.2023.102323. Epub 2023 May 17.
The bromodomain acts to recognize acetylated lysine in histones and transcription proteins and plays a fundamental role in chromatin-based cellular processes including gene transcription and chromatin remodeling. Many bromodomain proteins, particularly the bromodomain and extra terminal domain (BET) protein BRD4 have been implicated in cancers and inflammatory disorders and recognized as attractive drug targets. Although clinical studies of many BET bromodomain inhibitors have made substantial progress toward harnessing the therapeutic potential of targeting the bromodomain proteins, the development of this new class of epigenetic drugs is met with challenges, especially on-target dose-limiting toxicity. In this review, we highlight the current development of new-generation small molecule inhibitors for the BET and non-BET bromodomain proteins and discuss the research strategies used to target different bromodomain proteins for a wide array of human diseases including cancers and inflammatory disorders.
溴结构域能识别组蛋白和转录蛋白上的乙酰化赖氨酸，在基于染色质的细胞过程中发挥着基本作用，包括基因转录和染色质重塑。许多溴结构域蛋白，特别是溴结构域和末端结构域（BET）蛋白 BRD4，与癌症和炎症性疾病有关，被认为是有吸引力的药物靶点。尽管许多 BET 溴结构域抑制剂的临床研究在利用靶向溴结构域蛋白的治疗潜力方面取得了重大进展，但这类新型表观遗传药物的发展仍面临挑战，尤其是在靶毒性方面。在这篇综述中，我们重点介绍了新一代 BET 和非 BET 溴结构域蛋白小分子抑制剂的发展，并讨论了用于针对包括癌症和炎症性疾病在内的多种人类疾病的不同溴结构域蛋白的研究策略。
