A pharmacological modality to sequester homomeric proteins

Molecules that facilitate protein-protein interactions are immensely impactful. However, such compounds typically rely on accessory proteins to function, such as E3 ligases for targeted degradation, which may restrict their scope or lead to resistance. We alleviate the need for accessory proteins with a strategy that exploits protein symmetry as a selective vulnerability and is widely applicable because of the ubiquitous nature of homomeric proteins. We target homomeric proteins with PINCHs (polymerization-inducing chimeras)-bifunctional molecules composed of two linked ligands that bridge homomers and trigger their supramolecular assembly into insoluble polymers. We design PINCHs that achieve efficient polymerization of four targets. In cells, we observed that a PINCH targeting Keap1 exhibited a longer duration of action and a PINCH targeting BCL6 displayed selective lowering of B cell viability compared to their monomeric parents. Our results highlight PINCHs as a novel and general strategy to modulate and knock out protein function.