Targeting bromodomain-containing proteins: research advances of drug discovery
靶向含溴结构域蛋白：药物发现研究进展
📄 英文摘要 English Abstract
Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic.
📄 中文摘要 Chinese Abstract
📋 英文结构化总结 English Structured Summary
全文整理
Background:
Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials.
Methods:
N/A - Review article
Results:
Key findings include the classification of BDs into eight subtypes and BCPs into BET and non-BET families based on number of BDs, domain architecture, and homology. Structurally, BDs share a conserved four-helix fold (αZ, αA, αB, αC) linked by ZA and BC loops, forming a hydrophobic cavity that recognizes acetylated lysine via hydrogen bonding with a conserved asparagine residue. Small molecule BDs inhibitors such as (+)-JQ1, I-BET762, I-BET151, and RVX-208 bind by mimicking this KAc binding mode, while non-KAc mimetic molecules like MS7972 and ZL0590 bind without a canonical hydrogen bond with the asparagine residue. The review covers development history, molecular structure, biological activity, interaction with BCPs, and therapeutic potentials of these drugs.
Data Summary:
Quantitative results include that there are 61 types of BDs in humans, contained in 46 different BCPs. The structural analysis used 33 crystal structures and 4 nuclear magnetic resonance (NMR) models to uncover comprehensive structural features. BDs consist of approximately 110 amino acids each. The BET family in mammals comprises BRD2, BRD3, BRD4, and BRDT, while the non-BET family includes histone acetyl-transferases, histone methyl-transferases, ATP-dependent chromatin remodeling complexes, helicases, transcriptional coactivators, and nuclear-scaffolding proteins.
Conclusions:
This paper provides a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials. Additionally, current challenges, issues to be addressed, and future research directions for the development of BCPs inhibitors are discussed. Lessons learned from successful or unsuccessful development experiences will facilitate further development of efficient, selective, and less toxic inhibitors for eventual clinical application.
Practical Significance:
Real-world applications include therapeutic strategies for cancers, inflammation, cardiovascular diseases, and viral infections through inhibiting or downregulating BCPs to interfere with pathogenic gene transcription. The lessons from development of inhibitors and degraders can guide the creation of more efficient, selective, and less toxic BCP inhibitors, ultimately achieving drug application in the clinic.
📋 中文结构化总结 Chinese Structured Summary
背景:
溴结构域（BD）是一种进化上保守的蛋白质模块，存在于46种不同的含溴结构域蛋白（BCPs）中。BD作为乙酰化赖氨酸残基（KAc）的特异性识别元件，在转录调控、染色质重塑、DNA损伤修复及细胞增殖中发挥关键作用。另一方面，研究表明BCPs参与了多种疾病的发病机制，包括癌症、炎症、心血管疾病和病毒感染。过去十年间，研究人员通过抑制BCPs的活性或下调其表达来干扰致病基因的转录，从而为相关疾病带来了新的治疗策略。越来越多强效的BCPs抑制剂和降解剂已被开发出来，其中部分已进入临床试验阶段。
方法:
不适用——综述类文章
结果:
主要发现包括：根据BD的数量、结构域组成和同源性，将BD分为八种亚型，将BCPs分为BET和非BET家族。在结构上，BD具有保守的四螺旋折叠结构（αZ、αA、αB、αC），由ZA环和BC环连接，形成一个疏水空腔，通过保守的天冬酰胺残基与乙酰化赖氨酸形成氢键实现识别。小分子BD抑制剂如(+)-JQ1、I-BET762、I-BET151和RVX-208通过模拟KAc的结合模式发挥作用，而非KAc模拟分子如MS7972和ZL0590则在不与天冬酰胺残基形成典型氢键的情况下结合。本综述涵盖了这些药物的研发历程、分子结构、生物学活性、与BCPs的相互作用及治疗潜力。
数据概要:
定量结果显示，人类中共有61种BD，分布于46种不同的BCPs中。结构分析采用了33个晶体结构和4个核磁共振（NMR）模型，以揭示全面的结构特征。每个BD约由110个氨基酸组成。哺乳动物的BET家族包括BRD2、BRD3、BRD4和BRDT，而非BET家族则包括组蛋白乙酰转移酶、组蛋白甲基转移酶、ATP依赖性染色质重塑复合物、解旋酶、转录共激活因子和核支架蛋白。
结论:
本文对抑制或下调BCPs的药物研究最新进展进行了全面综述，重点涵盖研发历程、分子结构、生物学活性、与BCPs的相互作用及治疗潜力。此外，还讨论了BCPs抑制剂研发中当前面临的挑战、待解决的问题及未来研究方向。从成功或失败的研发经验中汲取的经验教训，将有助于进一步开发高效、高选择性且低毒性的抑制剂，最终实现临床应用。
实际意义:
实际应用包括通过抑制或下调BCPs来干扰致病基因转录，从而为癌症、炎症、心血管疾病和病毒感染提供治疗策略。从抑制剂和降解剂研发中获得的经验可为开发更高效、高选择性且低毒性的BCPs抑制剂提供指导，最终实现药物在临床中的应用。