Issue 11, 2023

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

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.

Graphical abstract: Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead

Supplementary files

Article information

Article type
Paper
Submitted
26 jun 2023
Accepted
31 ago 2023
First published
31 ago 2023
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2023,4, 906-912

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

R. P. Nowak, L. Ragosta, F. Huerta, H. Liu, S. B. Ficarro, J. T. Cruite, R. J. Metivier, K. A. Donovan, J. A. Marto, E. S. Fischer, B. L. Zerfas and L. H. Jones, RSC Chem. Biol., 2023, 4, 906 DOI: 10.1039/D3CB00103B

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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