Leveraging targeted protein ldegradation for G protein-coupled receptors: the development of CCR2 molecular degraders

Essa, K.; Zacarias, N.V.O.; Roth, S.; Xin, B.T.; Winter, S. de; Horst, C. van der; Bleijs, B.; Heiden, R.A. de; Voulgaraki, R.; Neubert, E.; Ovaa, H.; Danen, E.H.J.; Mulder, M.P.C.; Moreau, K.; Es, D. van der; Heitman, L.H.

doi:doi:10.1021/acs.jmedchem.5c02920

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...Show moreTargeted 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.Show less

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Leveraging targeted protein ldegradation for G protein-coupled receptors: the development of CCR2 molecular degraders