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 (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.