Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3

Sascha Röth, Nur Mehpare Kocaturk, Preethi S. Sathyamurthi, Bill Carton, Matthew Watt, Thomas J. Macartney, Kwok-Ho Chan, Albert Isidro-Llobet, Agnieszka Konopacka, Markus A. Queisser, Gopal P. Sapkota (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
79 Downloads (Pure)


Targeted protein degradation (TPD), induced by enforcing target proximity to an E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins. However, out of over 600 E3 ligases encoded by the human genome, just over 10 E3 ligases are currently utilized for TPD. Here, using the affinity-directed protein missile (AdPROM) system, in which an anti-GFP nanobody was linked to an E3 ligase, we screened over 30 E3 ligases for their ability to degrade 4 target proteins, K-RAS, STK33, β-catenin, and FoxP3, which were endogenously GFP-tagged. Several new E3 ligases, including CUL2 diGly receptor KLHDC2, emerged as effective degraders, suggesting that these E3 ligases can be taken forward for the development of small-molecule degraders, such as proteolysis targeting chimeras (PROTACs). As a proof of concept, we demonstrate that a KLHDC2-recruiting peptide-based PROTAC connected to chloroalkane is capable of degrading HALO-GFP protein in cells.
Original languageEnglish
Pages (from-to)1261-1276.e7
Number of pages23
JournalCell Chemical Biology
Issue number10
Early online date7 Aug 2023
Publication statusPublished - 19 Oct 2023


  • RAS
  • STK33
  • β-catenin
  • FoxP3
  • KLHDC2
  • TPD
  • degron
  • E3 ligase
  • cancer

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmacology


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