Clues for glues: from serendipity to nature’s blueprints in degrader discovery

Molecular glue degraders (MGDs) are small molecules that promote interactions between an E3 ligase and a target protein, reconfiguring recognition to trigger proteasome-mediated degradation. Their discovery has so far been largely serendipitous - either recognized in retrospect or uncovered through 'needle-in-a-haystack' screening - but systematic strategies are beginning to emerge. This review frames two complementary routes for discovery. The first views MGDs as modular - typically anchored on either the ligase or the target - which allows the chemical search space to be biased toward such anchoring. Ligase-directed strategies derivatize known ligase binders, as demonstrated for cereblon (CRBN) and now beyond. Conversely, recent target-directed strategies remodel inhibitors into glues through solvent-exposed elaboration, effectively inverting the classical design paradigm. Both approaches tilt discovery toward chemotypes more likely to yield glue activity. Second, biology provides its own guideposts: certain protein pairs appear especially predisposed to stabilization. Endogenous degrons, mutational lesions, and transferable 'glueprints' of surface topology all point to contexts in which small molecules might act as functional surrogates - repairing hypomorphs, mimicking hypermorphs, or creating neomorphs. MGDs, therefore, exemplify how small molecules can reprogram recognition logic by transforming latent compatibilities into selective degradation. Together, these insights help rationalize past discoveries and suggest possible blueprints for more systematic ones ahead.