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Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, ß-catenin, and FoxP3.
Röth, Sascha; Kocaturk, Nur Mehpare; Sathyamurthi, Preethi S; Carton, Bill; Watt, Matthew; Macartney, Thomas J; Chan, Kwok-Ho; Isidro-Llobet, Albert; Konopacka, Agnieszka; Queisser, Markus A; Sapkota, Gopal P.
Affiliation
  • Röth S; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
  • Kocaturk NM; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
  • Sathyamurthi PS; Protein Degradation Group, Medicines Research Centre, GSK, Gunnels Wood Road, Stevenage, UK.
  • Carton B; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
  • Watt M; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
  • Macartney TJ; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
  • Chan KH; Protein Degradation Group, Medicines Research Centre, GSK, Gunnels Wood Road, Stevenage, UK.
  • Isidro-Llobet A; Chemical Biology, Medicines Research Centre, GSK, Gunnels Wood Road, Stevenage, UK.
  • Konopacka A; Protein Degradation Group, Medicines Research Centre, GSK, Gunnels Wood Road, Stevenage, UK.
  • Queisser MA; Protein Degradation Group, Medicines Research Centre, GSK, Gunnels Wood Road, Stevenage, UK.
  • Sapkota GP; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK. Electronic address: g.sapkota@dundee.ac.uk.
Cell Chem Biol ; 30(10): 1261-1276.e7, 2023 10 19.
Article in En | MEDLINE | ID: mdl-37591251
ABSTRACT
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, ß-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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Beta Catenin Type of study: Diagnostic_studies Limits: Humans Language: En Journal: Cell Chem Biol Year: 2023 Document type: Article Affiliation country: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Beta Catenin Type of study: Diagnostic_studies Limits: Humans Language: En Journal: Cell Chem Biol Year: 2023 Document type: Article Affiliation country: United kingdom