Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity

Abstract

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.