Traditional small-molecule drug discovery efforts are almost exclusively focused on directly regulating protein activity through ligand/inhibitor development. More recently, bifunctional degrader molecules known as PROteolysis TArgeting Chimeras (PROTACs™) or Chemical Inducers of DEgradation (CIDEs) have emerged as a powerful way to regulate protein function by inducing selective proteasomal degradation of target proteins. However, the development of CIDE molecules into viable drug candidates still poses several challenges, including their relatively high molecular weight and poor cell permeability. Current CIDE molecules are composed of three components, an E3 ligase-binding moiety, a protein target-binding region, and a variable linear linker element. A potentially important aspect of efficient CIDE design is the stabilization of the ternary complex between the target protein and the E3 ligase. However, many CIDE molecules have flexible linkers and are thus not ideally suited for stabilization of such ternary complexes. Based on structure-guided designs we generated the first peptide-based macrocyclic BRD4/VHL CIDE molecules, which exhibit more constrained structures with improved stabilization of the BRD4/VHL/CIDE ternary complex than their linear counterparts. Moreover, by applying property-based optimization we succeeded in transforming the initial macrocycles into cell-permeable lead molecules that induce degradation of BRD4 at single-digit