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bioRxiv · 10.64898/2026.01.28.702440

Harnessing FBXO31 with terminal amide-functionalized molecules for targeted protein degradation

Zhang, C.·Jin, X.·Zhou, C.·Martin, J. M.·Riha, I. A.·Zhang, X.
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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 rapid and potent target degradation. Mechanistic studies confirm FBXO31-mediated ternary complex formation and identify key residues in FBXO31 required for recruiter engagement and target degradation. We further show that an FBXO31-based multi-kinase degrader exhibits a distinct and broader degradation profile than a CRBN-based degrader, highlighting a potentially expanded degradable target space beyond CRBN.

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Zhang, C., Jin, X., Zhou, C., Martin, J. M., Riha, I. A., Zhang, X.. 2026-01-29. Harnessing FBXO31 with terminal amide-functionalized molecules for targeted protein degradation. https://doi.org/10.64898/2026.01.28.702440

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