Bromodomain和Extra Terminal (BET)蛋白的小分子PROTAC降解物研究进展

Q1 Pharmacology, Toxicology and Pharmaceutics

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI:10.1016/j.ddtec.2019.04.001

Chao-Yie Yang, Chong Qin, Longchuan Bai, Shaomeng Wang

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引用次数: 76

摘要

PROteolysis TArgeting Chimeric (PROTAC)概念为发现和开发一种涉及诱导蛋白质降解的全新治疗方法提供了机会。BET蛋白由BRD2、BRD3、BRD4和睾丸特异性BRDT蛋白组成，是表观遗传读取器和主转录共激活因子。基于可用的、有效的和选择性的BET抑制剂，已经报道了非常有效和有效的BET蛋白的小分子PROTAC降解剂。BET降解剂与BET抑制剂在细胞效力、表型效应、药代动力学性质和毒性方面不同。在此，我们综述了BET降解物以及在细胞和动物模型中与BET抑制剂相比，BET降解物观察到的不同结果。

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Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins — A review

The PROteolysis TArgeting Chimeric (PROTAC) concept has provided an opportunity for the discovery and development of a completely new type of therapy involving induction of protein degradation. The BET proteins, comprised of BRD2, BRD3, BRD4 and the testis-specific BRDT protein, are epigenetic readers and master transcription coactivators. Extremely potent and efficacious small-molecule PROTAC degraders of the BET proteins, based on available, potent and selective BET inhibitors, have been reported. BET degraders differ from BET inhibitors in their cellular potency, phenotypic effects, pharmacokinetic properties and toxicity profiles. Herein, we provide a review of BET degraders and the differential outcome observed in the cellular and animal models for BET degraders in comparison to BET inhibitors.

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Drug Discovery Today: Technologies Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

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期刊介绍： Discovery Today: Technologies compares different technological tools and techniques used from the discovery of new drug targets through to the launch of new medicines.