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Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

Henning, Nathaniel, Manford, Andrew, Spradlin, Jessica, Brittain, Scott, Zhang, Erika, McKenna, Jeffrey, Tallarico, John, Schirle, Markus, Rape, Michael and Nomura, Daniel (2021) Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications. Journal of the American Chemical Society, 144 (2). pp. 701-708. ISSN 0002-7863

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Proteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularity of TPD approaches in drug discovery, only a small number E3 ligase recruiters are available for the >600 E3 ligases that exist in human cells. Here, we have discovered a cysteine-reactive covalent ligand EN106 that targets FEM1B, an E3 ligase recently discovered to be critical in cellular reductive stress response. EN106, through targeting cysteine C186, disrupts FEM1B substrate recognition of FNIP1. We further establish that EN106 can be used as a covalent recruiter for FEM1B in TPD applications, in which we demonstrate that a PROTAC linking EN106 to the BET Bromodomain inhibitor JQ1 leads to the selective NEDDylation, proteasome, and FEM1B-dependent degradation of BRD4 in cells. Our study showcases a covalent ligand that targets a substrate recognition site within the E3 ligase FEM1B involved in reductive stress response and highlights the utility of covalent ligand screening in expanding the arsenal of E3 ligase recruiters that can be deployed for TPD applications.

Item Type: Article
Date Deposited: 15 Feb 2022 00:45
Last Modified: 15 Feb 2022 00:45


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