Drugging the undruggable: Chemical and biological insights into molecular glues in the pipeline

Abstract

Recent advances in drug discovery have given rise to molecular glues, which present a unique chance to target functional proteins that were previously thought to be "undruggable" by traditional techniques. Molecular glues bridge the gap between biologics and conventional small-molecule protein inhibitors. They combine the advantageous pharmacokinetic profile of conventional small-molecule inhibitors with the target specificity of biologics in an innovative way. Furthermore, molecular glues get beyond the main drawbacks of other therapeutic approaches, namely the absence of distinct binding sites in difficult-to-target proteins for conventional small-molecule inhibitors and the drug-induced immunogenicity of biologics. This review delves into the conceptual and mechanistic underpinnings of molecular glues, from the accidental discovery of early immunomodulators like cyclosporin A through the investigation of thalidomide as a glue degrader to the current clinical evaluation of a diverse pipeline of structurally and mechanistically distinct molecular glues. The review identifies important binding motifs, common binding patterns, and hotspots at glue-induced protein interfaces through crystallographic data analysis of glue-induced ternary complexes. We aimed at broadening the therapeutic horizon of precision medicine by providing medicinal chemists with the fundamental concepts required for the rational design of next-generation molecular glues through the establishment of a structure-guided framework.