Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications
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Abstract
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 of 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 as the critical component of the cellular response to reductive stress. By targeting C186 in FEM1B, EN106 disrupts recognition of the key reductive stress substrate of FEM1B, FNIP1. We further establish that EN106 can be used as a covalent recruiter for FEM1B in TPD applications by demonstrating that a PROTAC linking EN106 to the BET bromodomain inhibitor JQ1 or the kinase inhibitor dasatinib leads to the degradation of BRD4 and BCR-ABL, respectively. Our study showcases a covalent ligand that targets a natural E3 ligase-substrate binding site and highlights the utility of covalent ligand screening in expanding the arsenal of E3 ligase recruiters suitable for TPD applications.
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Covalent drug discovery platforms have facilitated expansion of targeted protein degradation by enabling discovery of covalent recruiters against E3 ubiquitin ligases.
“Covalent drug discovery platforms have facilitated the expansion of targeted protein degradation approaches by enabling the discovery of covalent recruiters against E3 ubiquitin ligases14,187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [193]
Since 2019, covalent recruiters have been used to validate a large proportion of E3 ligases harnessed for targeted protein degradation, including RNF114, RNF4, DCAF16, DCAF11, KEAP1 and FEM1B.
“Since 2019, covalent recruiters have been used to validate a large proportion of the E3 ligases that have been harnessed for targeted protein degradation, including RING finger protein 114 (RNF114), RNF4, DDB1 and CUL4-associated factor 16 (DCAF16), DCAF11, KEAP1 and, most recently, fem-1 homologue B (FEM1B)187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [193]
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- Authors
- Henning, N. J., Manford, A. G., Spradlin, J. N., Brittain, S. M., Zhang, E., McKenna, J. M., Tallarico, J. A., Schirle, M., Rape, M., & Nomura, D. K.
- Affiliations
- Innovative Genomics Institute (US)
- Howard Hughes Medical Institute (US)
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, California 94720, United States
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, United States
- Corresponding author
- Nomura, Daniel K.
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-01-07
- Volume
- 144
- Issue
- 2
- Pages
- 701-708
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC8928484
- OpenAlex
- W4220769998
- Cited by
- 221
- References
- 22
- Citations by year
- 2026: 35 · 2025: 47 · 2024: 49 · 2023: 46 · 2022: 37 · 2021: 6 · 2014: 1
- FWCI
- 14.94
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA240981)
- Mark Foundation For Cancer Research
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- FEM1B, E3 ubiquitin ligase, targeted protein degradation, reductive stress, FNIP1, BRD4 degradation, dasatinib, JQ1
- MeSH terms
- Dasatinib, Acetamides, Bromodomain Containing Proteins, Animals, Azepines, Binding Sites, Carrier Proteins, Cell Line, Cysteine, Humans, Protein Binding, Recombinant Proteins, Transcription Factors, Triazoles, Fusion Proteins, bcr-abl, Cell Cycle Proteins, Ubiquitin-Protein Ligase Complexes, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Mice, Proteolysis
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