Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy
- 1The Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
Abstract
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.
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BibTeX
@article{kashkush2026molecular,
title = {{Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy}},
author = {Aseel Kashkush and Kisanet Tadesse and Binyamin Insler and Raphael I. Benhamou},
journal = {npj Drug Discovery},
year = {2026},
month = oct,
doi = {10.1038/s44386-026-00087-w},
url = {https://doi.org/10.1038/s44386-026-00087-w},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy
AU - Aseel Kashkush
AU - Kisanet Tadesse
AU - Binyamin Insler
AU - Raphael I. Benhamou
PY - 2026
DA - 2026/10/26
JO - npj Drug Discovery
DO - 10.1038/s44386-026-00087-w
UR - https://doi.org/10.1038/s44386-026-00087-w
AB - 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.
SN - 3005-1452
ER -