硼替佐米和其衍生物是强大的癌症治疗药物，也是最为理解的分子黏附脱附剂（Molecular Glue Degraders，MGDs）之一。这些药物通过选择性重编程E3泛素连接酶 cereblon（CRBN）来使靶蛋白经泛素蛋白酶体系降解。MGDs在E3连接酶表面上创建了新的识别界面，与新的底物进行诱导性蛋白质相互作用。对其作用机制的分子洞察力为利用G-Loop这一特定识别基序接触众多靶点开辟了令人激动的机会。我们的分析显示，目前基于CRBN的MGDs原则上可以识别包含G-Loop的人类蛋白组中的2500多个蛋白质。我们回顾了在CRBN和其MGD诱导的新底物之间调控特异性方面的最新进展，推导出了一系列简单的相互作用规则。我们得出结论，合理的MGD设计工作将实现对更多蛋白质的选择性降解，将该治疗模式扩展到更多疾病领域。《药理学与毒理学年度评论》（Annual Review of Pharmacology and Toxicology）第64卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates以获取修订估计信息。

Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.