Development of Ligands for the von Hippel-Lindau E3 Ligase and Their Use in PROTACs, Small Molecule Inducers of Protein Degradation.

摘要

Chapter 1 provides general background of the ubiquitin proteasome system and a summary of inhibitors targeting this system. It then introduces the von Hippel-Lindau tumor suppressor (VHL), a component of a multi-subunit E3 ligase, providing rationale for the development of small molecule inhibitors for use as biological probes or as a possible target for the treatment of anemia. Finally, it introduces PROTACs, which are capable of inducing degradation of targeted proteins by recruiting E3 ligases through the use of a peptidic or small molecule ligand. Chapter 2 describes our strategy of designing small molecule ligands for VHL containing a hydroxyproline scaffold. It then describes the development of the first small molecule ligands, which competitively inhibit the VHL interaction with a peptide derived from its target, HIF 1 α. Chapter 3 describes further VHL ligand optimization and presents preliminary cell-based results showing that these ligands are capable of inhibiting VHL, leading to HIF 1 α stabilization. Finally, Chapter 4 describes the incorporation of the VHL ligands into PROTACs, and the optimization of these PROTACs for the degradation of a model target protein, HaloTag7-GFP. This model system will help further develop PROTACs into more useful probes for the effective degradation of multiple targets in vivo.