Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy

The cannabinoid receptor type 1 (CB₁R), a G protein-coupled receptor within the endocannabinoid system, has been implicated in oncogenic signaling and cancer progression. Here, we developed a series of compact covalent molecular glue degraders designed to reduce CB₁R abundance by recruiting components of the ubiquitin-proteasome system. Using rimonabant as a CB₁R-binding scaffold, we generated small molecules incorporating electrophilic E3 ligase-recruiting handles and identified MG-CB2 as the most active degrader. MG-CB2 induced concentration- and time-dependent depletion of CB₁R in MCF-7 breast cancer and HepG2 hepatocellular carcinoma cells. Proteasome inhibition blocked MG-CB2-mediated CB₁R loss, while RNF126 knockdown abrogated degradation, supporting a proteasome- and RNF126-dependent mechanism. Rimonabant competition and cellular thermal shift experiments further supported cellular engagement of CB₁R by MG-CB2. CB₁R degradation was accompanied by modulation of CB₁R-associated signaling, including reduced phosphorylation of ERK and mTOR and decreased BCL2 expression, along with reduced cancer-cell viability and migration. These findings establish covalent molecular glue-mediated degradation as a strategy for modulating CB₁R abundance and signaling and expand the application of targeted protein degradation to a transmembrane GPCR.