Biological and Medicinal Chemistry

Self-Assembly of Proteolysis Targeting Chimeras Via Reversible Bioorthogonal Reactions



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.


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Supplementary material

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Supplementary Information
Supplementary data and full experimental protocols.