Nature takes advantage of induced proximity to perform various functions. Taking inspiration from nature, we can also trigger desired biological processes using bifunctional small molecules that artificially induce proximity. For example, bifunctional small molecules have been designed to trigger the ubiquitin-dependent proteasomal degradation of intracellular proteins. Now, recent classes of bifunctional compounds have been developed to degrade extracellular targets, membrane proteins, damaged organelles, and RNA by recruiting alternative degradation pathways. In addition to inducing degradation, bifunctional modalities can change phosphorylation and glycosylation states to evoke a biological response. In this review, we highlight recent advances in these innovative classes of compounds that build on a rich history of chemical inducers of dimerization. We anticipate that more bifunctional molecules, which induce or remove posttranslational modifications, to endow neo-functionalities will emerge.

大自然利用感应接近来执行各种功能。从大自然中汲取灵感，我们还可以使用人工诱导接近的双功能小分子来触发所需的生物过程。例如，双功能小分子已被设计为触发细胞内蛋白质的泛素依赖性蛋白酶体降解。现在，最近开发了一类双功能化合物，通过招募替代降解途径来降解细胞外靶标、膜蛋白、受损细胞器和 RNA。除了诱导降解外，双功能模式还可以改变磷酸化和糖基化状态以引起生物反应。在这次审查中，我们强调了这些创新化合物类别的最新进展，这些化合物建立在二聚化化学诱导剂的丰富历史之上。我们预计会出现更多的双功能分子，它们会诱导或去除翻译后修饰以赋予新功能。