Arena BioWorks, Broad Institute, Harvard University, Cambridge, MA, USA.
Cell Chem Biol. 2024 Jun 20;31(6):1050-1063. doi: 10.1016/j.chembiol.2024.05.004. Epub 2024 Jun 10.
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.
这一看法探讨了分子胶和双功能化合物——诱导邻近的化合物，并提供了一个理解和利用它们与热点、错义突变和翻译后修饰（PTMs）相似性的框架。这一观点也与分子内胶有关，其中化合物诱导同一蛋白质的不同结构域之间的接触。本文还介绍了这些化合物的历史背景，表明该领域已经从针对天然蛋白质的分子胶，发展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，形成了一个完整的循环。本文还展示了现代筛选方法和针对预选靶蛋白的数据分析，可以产生协同分子胶或诱导邻近的双功能化合物，从而实现新的功能结果。
