Harnessing FBXO31 with Terminal Amide-Functionalized Molecules for Targeted Protein Degradation

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.