This Perspective explores molecular glues and bifunctional compounds—proximity-inducing compounds—and offers a framework to understand and exploit their similarity to hotspots, missense mutations, and posttranslational modifications (PTMs). This view is also shown to be relevant to intramolecular glues, where compounds induce contacts between distinct domains of the same protein. A historical perspective of these compounds is presented that shows the field has come full circle from molecular glues targeting native proteins, to bifunctionals targeting fusion proteins, and back to molecular glues and bifunctionals targeting native proteins. Modern screening methods and data analyses with pre-selected target proteins are shown to yield either cooperative molecular glues or bifunctional compounds that induce proximity, thereby enabling novel functional outcomes.

中文翻译：

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分子胶和双功能化合物：基于诱导接近的治疗方式


本视角探讨了分子胶和双功能化合物（邻近诱导化合物），并提供了一个框架来理解和利用它们与热点、错义突变和翻译后修饰 (PTM) 的相似性。这一观点也被证明与分子内胶有关，其中化合物诱导同一蛋白质的不同结构域之间的接触。提出了这些化合物的历史视角，表明该领域已经从针对天然蛋白质的分子胶，到针对融合蛋白的双功能化合物，再回到针对天然蛋白质的分子胶和双功能化合物。现代筛选方法和使用预选目标蛋白的数据分析显示可以产生协同分子胶或诱导接近的双功能化合物，从而实现新的功能结果。