Proximity Inducing Molecules: Molecular Glues and Their Mimics for Targeted Protein Degradation

Over the past century, one of the most enduring challenges in drug discovery has been the large proportion of the human proteome considered “undruggable.” The key reasons are twofold: most protein surfaces are relatively flat, and many proteins are unstructured and highly flexible. As a result, over 85% of human proteins remain inaccessible to traditional small-molecule inhibitors. Furthermore, conventional inhibitors are typically reversible, necessitating sustained high concentrations in the body to maintain therapeutic effects. To overcome these limitations, a transformative concept emerged—Targeted Protein Degradation (TPD)—which seeks not to inhibit but to eliminate disease-relevant proteins.

Although TPD is a relatively new approach, it has rapidly evolved into a major focus in medicinal chemistry. Among the different modalities, molecular glues represent a particularly promising class due to their favorable, drug-like properties. These small molecules induce proximity between two proteins, stabilizing interactions that would not naturally occur, ultimately leading to selective degradation of target proteins. Another importance is that they don’t need any classical binding pocket for attachment so the undruggable proteins can also be targeted. In this seminar, I will highlight the importance of molecular glues, from their conceptual origins to rational discovery strategies. The role of thalidomide as a pioneering molecular glue will be discussed, along with how chemical modifications and structure–activity relationships have enabled the design of next generation degraders. Finally, I will explore molecular glue mimics, with special emphasis on their role in cancer therapy and how the installation of specific chemical motifs (SuFEx) in peptide scaffolds provides a unique perspective from synthetic chemistry in controlling protein degradation.

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