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

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2024-03, Vol.67 (6), p.4641-4654
Main Authors: Shah, Rishi R., De Vita, Elena, Sathyamurthi, Preethi S., Conole, Daniel, Zhang, Xinyue, Fellows, Elliot, Dickinson, Eleanor R., Fleites, Carlos M., Queisser, Markus A., Harling, John D., Tate, Edward W.
Format: Article
Language:English
Subjects:
Ligands
Nuclear Proteins - metabolism
Proteolysis
Sulfinic Acids
Transcription Factors - metabolism
Ubiquitin-Protein Ligases - metabolism
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Summary:Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or the androgen receptor without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design, expanding the substrate scope of covalent E3 ligase PROTACs.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c02123