Harnessing FBXO31 with Terminal Amide-Functionalized Molecules for Targeted Protein Degradation
Abstract
Targeted protein degradation (TPD) is a powerful strategy for controlling protein abundance. Here, we establish FBXO31 as a TPD-competent E3 ligase by exploiting its recognition of C-terminal amide-bearing degrons. Using an amidated Ala-Phe motif as a chemical recruiter, multiple small-molecule binders can be transformed into FBXO31-dependent degraders that induce the rapid and potent degradation of FKBP12, multiple kinases, and BET proteins BRD2, BRD3, and BRD4. Mechanistic studies confirm FBXO31-mediated ternary complex formation and identify key residues in FBXO31 required for recruiter engagement and target degradation.
Fields of Study & Subjects
Peptidase Inhibition and Analysis
Protein Degradation and Inhibitors
Click Chemistry and Applications
Publication details
- Journal / source
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Volume
- 148
- Issue
- 15
- Pages
- 15391–15396
- Publication date
- 10 April 2026
- Language
- EN