推荐的工具化合物:靶向BET溴结构域的噻吩并三唑二氮杂卓衍生化学探针。

Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains.

作者信息

Huang Chuhui, Harris Kate S, Siddiqui Ghizal, Jörg Manuela

机构信息

Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

Drug Delivery, Disposition & Dynamics, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

出版信息

ACS Pharmacol Transl Sci. 2025 Mar 14;8(4):978-1012. doi: 10.1021/acsptsci.4c00726. eCollection 2025 Apr 11.

Abstract

Thienotriazolodiazepines, including (+)-JQ1 (), are well-known inhibitors of the bromodomain (BD) and extra-terminal domain (BET) family of proteins. Despite the suboptimal physicochemical properties as a drug candidate, such as poor solubility and half-life, (+)-JQ1 () has proven as an effective chemical probe with high target potency and selectivity. (+)-JQ1 () and (+)-JQ1-derived chemical probes have played a vital role in chemical biology and drug discovery over the past decade, which is demonstrated by the high number of impactful research studies published since the disclosure of (+)-JQ1 ( in 2010. In this review, we discuss the development of (+)-JQ1-derivatized chemical probes over the past decade and their significant contribution to scientific research. Specifically, we will summarize the development of innovative label-free and labeled (+)-JQ1-derivatized chemical probes, such as bivalent, covalent, and photoaffinity probes as well as protein degraders, with a focus on the design of these chemical probes.

摘要

噻吩并三唑二氮杂卓类化合物,包括(+)-JQ1(),是众所周知的蛋白质溴结构域(BD)和额外末端结构域(BET)家族的抑制剂。尽管作为候选药物的物理化学性质欠佳,如溶解度和半衰期较差,但(+)-JQ1()已被证明是一种具有高靶点效力和选择性的有效化学探针。在过去十年中,(+)-JQ1()和源自(+)-JQ1的化学探针在化学生物学和药物发现中发挥了至关重要的作用,自2010年(+)-JQ1披露以来发表的大量有影响力的研究证明了这一点。在这篇综述中,我们讨论了过去十年中(+)-JQ1衍生化学探针的发展及其对科学研究的重大贡献。具体而言,我们将总结创新的无标记和标记的(+)-JQ1衍生化学探针的发展,如二价、共价和光亲和探针以及蛋白质降解剂,重点是这些化学探针的设计。

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