The establishment of the PROTAC strategy was further augmented by the finding of degrader compounds that became known as molecular glues. Molecular glues are monovalent small molecules (<500 Da) that reshape the surface of an E3 ligase receptor, promoting novel protein-protein interactions (PPIs). In contrast to the original PROTACs, in which two ligands are connected by a flexible linker which can twist and turn and allow the two proteins to form contacts, molecular glues were believed to more directly enhance complex formation between an E3 ligase and a target protein by squeezing between protein-protein interfaces and are generally defined as small molecules that interact with two protein surfaces to induce or enhance affinity of these two proteins to each other (Figure ). The term "molecular glue" was initially coined to describe the mechanism of action of cyclosporin A and FK506 inducing novel protein-protein associations. The molecular glue degraders such as thalidomide were discovered retrospectively, after their FDA approval and later detection of their immunomodulatory and anti-inflammatory activity. The E3 ligase cereblon was identified as the target of thalidomide and its analogues lenalidomide and pomalidomide, known as immunomodulatory imide drugs (IMiDs), with reference to cancer therapy. They are some of the founding examples of molecular glues for targeted degradation. In fact, recent structural and biophysical data have shown that PROTACs can function in the same way as molecular glues, inducing neo-PPIs between the E3 ligase and the target protein thus contributing to the formation of stable ternary complexes between neo-substrate, PROTAC, and E3 ligase. 31, 32 This way, the distinction between PROTACs and molecular glues becomes difficult to define.