A pharmacological modality to sequester homomeric proteins

Molecules that can perturb protein-protein interactions have an immense impact on chemical biology and therapeutics. However, such compounds typically rely on accessory proteins to function, such as E3 ligases in the case of targeted degradation, which may restrict their target and tissue scope or lead to resistance. Here we alleviate the need for accessory proteins with a novel pharmacological modality to knock-down protein function. Our strategy exploits protein symmetry as a selective vulnerability, and is widely applicable owing to the ubiquitous nature of homomeric proteins in cellular systems. We target homomeric proteins with PINCHs (Polymerization Inducing Chimeras) - bifunctional molecules composed of two linked ligands that act as bridges between homomers and trigger their supramolecular assembly into insoluble polymers. We design PINCHs that achieve efficient polymerization of three homomeric targets. In cells, we observed that a PINCH targeting Keap1 exhibited a longer duration of action compared to its monomeric inhibitor, and a PINCH targeting BCL6 displayed selective and improved B cell toxicity compared to its monomeric parent. Our results highlight PINCHs as a novel and general strategy to modulate and knock out protein function.