Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules for targeted protein degradation (TPD).
• Covalent PROTACs offer advantages but designing them with broad protein of interest (POI) scope is challenging.
• The Von Hippel-Lindau (VHL) E3 ligase is a common target for PROTAC development.

Purpose of the Study:

• To design and optimize novel covalent VHL ligands for PROTAC applications.
• To demonstrate the utility of these covalent ligands in bifunctional degraders.
• To expand the substrate scope of covalent E3 ligase PROTACs.

Main Methods:

• Structure-guided design of sulfonyl fluoride-based VHL ligands.
• Covalent modification of VHL at Ser110 within the HIF1α binding site.
• Incorporation of ligands into bifunctional degraders for targeted protein degradation.

Main Results:

• Successful design and optimization of covalent VHL ligands.
• Demonstrated targeted protein degradation of BRD4 and androgen receptor using the developed PROTACs.
• Established the first covalent VHL ligands for direct use in bifunctional degrader design.

Conclusions:

• The novel covalent VHL ligands are effective in PROTAC design.
• This work expands the applicability of covalent E3 ligase PROTACs.
• The findings provide a new strategy for developing targeted protein degraders.