Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead

13Citations
Citations of this article
35Readers
Mendeley users who have this article in their library.

Abstract

Many cereblon (CRBN) ligands have been used to develop proteolysis targeting chimeras (PROTACs), but all are reversible binders of the E3 ubiquitin ligase. We recently described the use of sulfonyl exchange chemistry to design binders that covalently engage histidine 353 in CRBN for the first time. Here we show that covalent CRBN ligands can be used to develop efficient PROTAC degraders. We demonstrate that the fluorosulfate PROTAC FS-ARV-825 covalently labels CRBN in vitro, and in cells the BRD4 degrader is insensitive to wash-out and competition by potent reversible CRBN ligands, reflecting enhanced pharmacodynamics. We anticipate that covalent CRBN-based PROTACs will enhance degradation efficiencies, thus expanding the scope of addressable targets using the heterobifunctional degrader modality.

Cite

CITATION STYLE

APA

Nowak, R. P., Ragosta, L., Huerta, F., Liu, H., Ficarro, S. B., Cruite, J. T., … Jones, L. H. (2023). Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead. RSC Chemical Biology, 4(11), 906–912. https://doi.org/10.1039/d3cb00103b

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free