{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "The Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Aseel Kashkush"
    },
    {
      "affs": [
        0
      ],
      "name": "Kisanet Tadesse",
      "orcid": "0009-0000-8677-2674"
    },
    {
      "affs": [
        0
      ],
      "name": "Binyamin Insler"
    },
    {
      "affs": [
        0
      ],
      "name": "Raphael I. Benhamou",
      "orcid": "0000-0003-1743-0886"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4mkd7w22wnkj4.bib",
  "cited_by": 0,
  "doi": "10.1038/s44386-026-00087-w",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710980/",
  "id": "4mkd7w22wnkj4",
  "issns": [
    "3005-1452"
  ],
  "landing_url": "https://doi.org/10.1038/s44386-026-00087-w",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7223655157",
  "pdf_url": "https://www.nature.com/articles/s44386-026-00087-w.pdf",
  "pmcid": "PMC13710980",
  "pmid": "42934270",
  "published": "2026-10-26",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/4mkd7w22wnkj4.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:50Z",
      "native_id": "PMC13710980",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s44386-026-00087-w"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy",
  "title_text": "Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:50Z",
  "url": "https://research.draconitic.com/paper/4mkd7w22wnkj4",
  "venue": "npj Drug Discovery",
  "versions": []
}