Reversible Assembly of Proteolysis Targeting Chimeras

PROteolysis TArgeting Chimeras (PROTACs) are of significantcurrentinterest for the development of probe molecules and drug leads. However,they suffer from certain limitations. PROTACs are rule-breaking moleculeswith sub-optimal cellular permeability, solubility, and other drug-likeproperties. In particular, they exhibit an unusual dose-responsecurve where high concentrations of the bivalent molecule inhibit degradationactivity, a phenomenon known as the hook effect. This will likelycomplicate their use in vivo. In this study, we explore a novel approachto create PROTACs that do not exhibit a hook effect. This is achievedby equipping the target protein and E3 ubiquitin ligase ligands withfunctionalities that undergo rapid and reversible covalent assemblyin cellulo. We report the development of Self-Assembled ProteolysisTargeting Chimeras that mediate the degradation of the Von Hippel-LindauE3 ubiquitin ligase and do not evince a hook effect.