Molecular glue degraders have incredible therapeutic potential, particularly considering delivering on the promise of degrading “undruggable” proteins. However, their discovery has thus far been largely serendipitous. We have established a scalable strategy toward glue degrader discovery that is based on chemical screening in cell models where many E3 ligases are functionally impaired. This approach led us to identify novel compounds that induce ubiquitination and degradation of neosubstrates via a molecular glue mechanism. Notably, we found chemical scaffolds functioning without the need of a dedicated substrate receptor, thus functionally segregating this mechanism from typical degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify molecular glues with nonobvious mechanisms at scale and thus empower future drug discovery efforts.