Targeted protein degradation (TPD) by PROteolysis TArgeting Chimeras (PROTACs) is of great interest for probe molecule and drug development. However, current bivalent PROTACs are rule-breaking molecules with sub-optimal cellular permeability, solubility, and other drug-like properties. In this study, we report a novel approach for TPD by Self-Assembled Proteolysis TArgeting Chimeras (SAPTACs) in which the target protein and E3 Ubiquitin ligase ligands assemble in cellulo via reversible, bioorthogonal reactions. SAPTACs that me-diate the degradation of the Von Hippel Landau (VHL) E3 Ubiquitin ligase are described. We show that pseu-do-homodimeric degraders for VHL can be assembled in situ through the interaction of VHL ligands linked to phenylboronic acid and catechol as well as to o-acetlyphenylboronic acid and an alkoxyamine. The efficiency of VHL degradation by these SAPTACs is linked to the strength of the reversible covalent interaction.
Supplementary data and full experimental protocols.