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Small-Molecule Approaches to Targeted Protein Degradation
Annual Review of Cancer Biology ( IF 4.7 ) Pub Date : 2021-03-04 , DOI: 10.1146/annurev-cancerbio-051420-114114
Tyler B. Faust 1, 2 , Katherine A. Donovan 1, 2 , Hong Yue 1, 2 , Philip P. Chamberlain 3 , Eric S. Fischer 1, 2
Affiliation  

Many essential biological processes are regulated through proximity, from membrane receptor signaling to transcriptional activity. The ubiquitin-proteasome system controls protein degradation, with ubiquitin ligases as the rate-limiting step. Ubiquitin ligases are commonly controlled at the level of substrate recruitment and, therefore, by proximity. There are natural and synthetic small molecules that also operate through induced proximity. For example, thalidomide is effective in treating multiple myeloma and functions as a molecular glue that stabilizes novel protein-protein interactions between a ubiquitin ligase and proteins not otherwise targeted by the ligase, leading to neo-substrate degradation. Emerging data on new degrader molecules have uncovered diverse mechanisms distinct from molecular glues, which often mirror the regulatory mechanisms that control substrate-ligase proximity in nature. In this review, we summarize our current understanding of biological and synthetic regulation of protein degradation and share our view on how these diverse mechanisms have inspired novel therapeutic directions.

中文翻译:


靶向蛋白质降解的小分子方法

从膜受体信号传导到转录活性,许多重要的生物学过程都通过邻近来调节。泛素-蛋白酶体系统控制蛋白质的降解,而泛素连接酶是限速步骤。泛素连接酶通常在底物募集水平上被控制,因此通过邻近性来控制。有天然的和合成的小分子,它们也通过诱导的接近而起作用。例如,沙利度胺可有效治疗多发性骨髓瘤,并起分子胶的作用,可稳定遍在蛋白连接酶与未由连接酶靶向的蛋白之间的新型蛋白-蛋白相互作用,从而导致新底物降解。关于新降解分子的新兴数据发现了与分子胶不同的多种机理,这些通常反映出自然界中控制底物-连接酶接近性的调节机制。在这篇综述中,我们总结了目前对蛋白质降解的生物学和合成调控的理解,并就这些不同的机制如何激发新的治疗方向分享了我们的观点。

更新日期:2021-03-05
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