The therapeutic potential of PROTACs
The therapeutic potential of PROTACs
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DOI：
10.1080/13543776.2021.1840553
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发表时间：
2021-01-11
影响因子：
6.6
通讯作者：
Harling, John D.
中科院分区：
文献类型：
--
作者：
Benowitz, Andrew B.;Jones, Katherine L.;Harling, John D.
简介：PROTAC代表一类新型的异双功能分子，其同时结合靶蛋白和E3连接酶复合物，导致泛素的转移并启动最终导致靶蛋白的蛋白酶体降解的过程。与抑制剂相比，这种作用机制赋予PROTAC以独特的方式调节靶生物学的能力，PROTAC作为治疗剂的发展有望产生治疗多种疾病的新药。涵盖领域：本综述包括2013年1月至2020年6月期间已公布的PCT（WO）专利申请。只有英文专利申请中的PROTAC降解靶蛋白的例子被认为在范围内，“PROTAC”的定义被限制为双功能分子，它包含一个特定降解靶点的离散结合元件，以及一个单独的离散E3连接酶结合部分。专家意见：要发挥PROTAC的巨大潜力，就需要开发与传统小分子抑制剂不同的PROTAC药物。PROTAC的模块化组成为确保强大的知识产权提供了机遇和挑战，我们设想，随着这一领域的成熟，对新奇的要求可能会发生变化。
Introduction: PROTACs represent a novel class of heterobifunctional molecules that simultaneously bind to a target protein and to an E3 ligase complex, resulting in the transfer of ubiquitin and initiating a process ultimately causing the proteasomal degradation of the target protein. This mechanism of action imbues PROTACs with the ability to modulate target biology in unique ways compared to inhibitors, and the development of PROTACs as therapeutic agents is expected to result in new medicines to treat multiple diseases.Areas covered: This review includes published PCT (WO) patent applications covering January 2013 through June 2020. Only English-language patent applications with exemplified PROTACs reported to degrade a target protein(s) were deemed in scope, and the definition of 'PROTAC' was restricted to a bifunctional molecule which contains a discrete binding element for a specific degradation target(s), as well as a separate discrete E3 ligase-binding moiety.Expert opinion: Delivering on the enormous potential of PROTACs will require the development of PROTAC medicines that are differentiated from traditional small-molecule inhibitors. The modular composition of PROTACs affords both opportunities and challenges in securing robust intellectual property, and we envision that requirements for novelty are likely to evolve as this area matures.