School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China.
Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China.
Future Med Chem. 2019 Nov;11(22):2919-2973. doi: 10.4155/fmc-2019-0159. Epub 2019 Nov 8.
Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure-activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.
目前，酶抑制剂和受体激动剂/拮抗剂等传统药物由于作用机制为占据驱动药理学，因此存在固有局限性。蛋白水解靶向嵌合体（PROTAC）由 E3 配体、连接接头和靶蛋白配体组成，是一种利用事件驱动作用模式特异性敲低靶蛋白的有吸引力的方法。连接接头的长度、亲水性和刚性在创建成功的 PROTAC 中起着重要作用。一些具有三唑接头的 PROTAC 已显示出有前景的抗癌活性。本综述提供了具有三唑骨架的 PROTAC 的概述，并讨论了其结构-活性关系。讨论了 PROTAC 发展中的重要里程碑，并对这种药物发现策略进行了批判性分析。
