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

9781303299698

1 online resource (335 p.)

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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 alpha. 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 alpha 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.

Books / Online / Dissertations & Theses

English

July 25, 2014

Thesis (Ph.D.)--Yale University, 2013.

Yale University. Chemistry.