Leveraging Targeted Protein Degradation for G Protein-Coupled Receptors: The Development of CCR2 Molecular Degraders
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 (<b>8</b>) 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 (<b>8</b>) 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.
Authors
- Laura H. Heitman (ORCID: https://orcid.org/0000-0002-1381-8464)
- Daan van der Es (ORCID: https://orcid.org/0000-0003-3662-8177)
- Erik H.J. Danen (ORCID: https://orcid.org/0000-0002-0491-6345)
- Cas van der Horst (ORCID: https://orcid.org/0000-0002-5859-5348)
- Natalia V. Ortiz Zacarı́as (ORCID: https://orcid.org/0000-0002-2012-5519)
- Sascha Röth (ORCID: https://orcid.org/0000-0001-7273-6701)
- Khaled Essa (ORCID: https://orcid.org/0000-0001-9090-3219)
- Monique P. C. Mulder (ORCID: https://orcid.org/0000-0001-5386-7132)
- Elsa Neubert (ORCID: https://orcid.org/0000-0003-4642-9112)
- Kévin Moreau (ORCID: https://orcid.org/0000-0002-3688-3998)
- Sabine de Winter (ORCID: https://orcid.org/0009-0002-1152-7994)
- Huib Ovaa (ORCID: https://orcid.org/0000-0002-0068-054X)
- Bente T.M. Bleijs
- Bo‐Tao Xin (ORCID: https://orcid.org/0000-0001-9170-5337)
- Richard A. de Heiden (ORCID: https://orcid.org/0000-0002-7125-840X)
- Rodanthi Voulgaraki
Institutions
- AstraZeneca (United Kingdom) (GB)
- Leiden University (NL)
- Leiden University Medical Center (NL)
- Oncode Institute (NL)
- AstraZeneca (Singapore) (SG)
- NOAA Chemical Sciences Laboratory (US)
- Centre for Human Drug Research (NL)
- National Patient Safety Foundation (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02920
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81