The Intersection of Allostery and Induced Proximity through the E3 Ligase Cereblon

Abstract Allostery modulates protein function through domains that are distinct from a protein’s orthosteric active site. In a therapeutic context, allosteric ligands provide mechanisms to overcome resistance, improve selectivity, and act cooperatively with orthosteric ligands. Separately, induced proximity modalities alter protein function by inducing an interaction between a target protein and an effector protein, like the E3 ligase substrate adapter cereblon (CRBN), which promotes the proteasomal degradation of the target. CRBN ligands that bind at the thalidomide-binding domain have seeded versatile chemical platforms for molecular glue degraders and proteolysis-targeting chimeras (PROTACs). CRBN gains its remarkable inducible substrate scope through conformational shifts that can be mediated by allosteric ligands to alter protein degradation outcomes. We merge the intersection of allostery with induced proximity modalities by examining it first in the context of allosteric pharmacology and second in the context of targeted protein degradation with CRBN, highlighting how lessons learned from allostery with other therapeutic targets could inform emerging opportunities for allosteric modulation of induced proximity events. This intersection of allostery and induced proximity at CRBN conceptually unites two major chemical means of changing protein fate, bringing the potential for highly selective and potent chemical modalities for a greater part of the proteome closer to reality.