2. Academic Validation
  3. Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation

Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation

  • Nat Commun. 2024 Jun 26;15(1):5409. doi: 10.1038/s41467-024-49739-3.
Chrysanthi Kagiou 1,  Jose A Cisneros 1,  Jakob Farnung 2,  Joanna Liwocha 2,  Fabian Offensperger 1,  Kevin Dong 3,  Ka Yang 3,  Gary Tin 1,  Christina S Horstmann 1 4,  Matthias Hinterndorfer 1,  Joao A Paulo 3,  Natalie S Scholes 1,  Juan Sanchez Avila 1,  Michaela Fellner 5,  Florian Andersch 5,  J Thomas Hannich 1,  Johannes Zuber 5,  Stefan Kubicek 1,  Steven P Gygi 3,  Brenda A Schulman 2,  Georg E Winter 6
Affiliations

Affiliations

  • 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.
  • 2 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 4 St. Anna Children's Cancer Research Institute, Vienna, Austria.
  • 5 Research Institute of Molecular Pathology, Vienna BioCenter, 1030, Vienna, Austria.
  • 6 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria. gwinter@cemm.oeaw.ac.at.
PMID: 38926334 DOI: 10.1038/s41467-024-49739-3
Abstract

Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 Ligases to induce their ubiquitylation and degradation by the Proteasome. Only a few of the approximately 600 human E3 Ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases. Here we identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12. SP3N features a minimal design, where a known FKBP12 ligand is appended with a flexible alkylamine tail that conveys degradation properties. We found that SP3N is a precursor and that the alkylamine is metabolized to an active aldehyde species that recruits the SCFFBXO22 Ligase for FKBP12 degradation. Target engagement occurs via covalent adduction of Cys326 in the FBXO22 C-terminal domain, which is critical for ternary complex formation, ubiquitylation and degradation. This mechanism is conserved for two recently reported alkylamine-based degraders of NSD2 and XIAP, thus establishing alkylamine tethering and covalent hijacking of FBXO22 as a generalizable TPD strategy.

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