2. Academic Validation
  3. Leveraging Targeted Protein Degradation for G Protein-Coupled Receptors: The Development of CCR2 Molecular Degraders

Leveraging Targeted Protein Degradation for G Protein-Coupled Receptors: The Development of CCR2 Molecular Degraders

  • J Med Chem. 2025 Dec 25;68(24):26525-26546. doi: 10.1021/acs.jmedchem.5c02920.
Khaled Essa 1,  Natalia V Ortiz Zacarías 1,  Sascha Roth 2,  Bo-Tao Xin 3,  Sabine de Winter 4,  Cas van der Horst 1,  Bente Bleijs 1,  Richard A de Heiden 1,  Rodanthi Voulgaraki 1,  Elsa Neubert 4,  Huib Ovaa 3,  Erik H J Danen 4,  Monique P C Mulder 3,  Kevin Moreau 2,  Daan van der Es 1,  Laura H Heitman 1 5
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
  • 2 Safety Innovation and PROTAC Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0SL, United Kingdom.
  • 3 Department of Cell and Chemical Biology, Chemical Immunology, Leiden University Medical Centre, Leiden 2333 ZC, The Netherlands.
  • 4 Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
  • 5 Oncode Institute, Leiden 2333 CC, The Netherlands.
PMID: 41381043 DOI: 10.1021/acs.jmedchem.5c02920
Abstract

Targeted protein degradation (TPD) is one of the most prominent and rapidly advancing modalities in drug discovery. However, only few degraders have been reported for the membrane-bound G protein-coupled receptors (GPCRs). Therefore, using CC Chemokine Receptor 2 (CCR2) as a GPCR model, we synthesized potential CCR2 molecular degraders. The putative proteolysis-targeting chimeras (PROTACs) employed an allosteric intracellular CCR2 ligand tethered to commonly used E3 Ligase ligands. Among these compounds, LUF7996 (8) demonstrated engagement of both CCR2 and the E3 ligase Cereblon and displayed sustained and concentration-dependent degradation of CCR2 over 24 h. Mechanistic studies revealed the reliance of LUF7996 on the lysosomal pathway to induce CCR2 degradation. Finally, LUF7996 (8) efficiently inhibited monocyte migration in a transwell assay. Collectively, the developed assessment workflow led to identification of the first CCR2 molecular degraders and has the potential to expand the repertoire of degraders targeting the pharmacologically rich GPCRs.

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