Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation
Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic degradation machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance the applicability of this strategy across various biological contexts. In this study, we discovered that a somatic mutant of FBXW7, R465C, can be exploited by heterobifunctional compounds for targeted protein degradation. This work demonstrates the potential of utilizing mutant E3 ligases that occur exclusively in diseased cells for TPD applications.
Authors
- Milad Rouhimoghadam
- Ananya A. Basu (ORCID: https://orcid.org/0000-0002-1427-5326)
- Justin M. Reitsma (ORCID: https://orcid.org/0000-0002-2700-6440)
- Xiaoyu Zhang (ORCID: https://orcid.org/0000-0002-0951-9664)
- Anil Vasudevan
- Chenlu Zhang (ORCID: https://orcid.org/0000-0002-6410-9692)
Institutions
- Northwestern University (US)
- AbbVie (United States) (US)
- IPM Institute of North America (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1021/jacs.4c17331
- Citations
- 6
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- Damon Runyon Cancer Research Foundation
- Chemistry of Life Processes Institute
- National Cancer Institute
- National Institute of General Medical Sciences