Primed for degradation: How weak protein interactions enable molecular glue degraders

Molecular glues are small drug-like molecules that induce de novo protein–protein interactions or facilitate pre-existing weak interactions between proteins. In the context of a ubiquitin ligase, such binding events frequently result in ubiquitination by proximity. Rational development of these transformative modalities, however, remains a major challenge. Here we review recent insights into molecular glues and the emerging design principles. Protein surfaces can similarly be complemented by mutations or compounds inducing binding and a resulting gain of functionality. When the interaction surface between two proteins is relatively small, or when the affinity between the proteins is otherwise weak, proportionally more binding energy will have to be provided by the compound to glue the proteins together. We suggest a simple thermodynamic model to rationalize molecular glue action facilitated by compounds and mutations.