Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse
Tumor recurrence is frequently attributed to drug-tolerant cancer cells. We previously demonstrated that downregulation of the Pregnane X Receptor (PXR, NR1I2) reduces chemoresistance and prevents colorectal cancer recurrence in xenograft mouse models. However, there is currently a lack of clinically-suitable PXR antagonists. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) which promotes polyubiquitination and degradation of the human PXR protein via E3 CRBN ubiquitin ligase and 26S proteasome pathways. JMV7048 selectively degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, with no impact on primary human hepatocytes. Notably, JMV7048 reduces PXR protein expression in drug-tolerant colon cancer cells, sensitizing them to chemotherapy and significantly delaying cancer relapse in xenografted nude mice. These findings suggest that PXR-targeting PROTACs may serve as novel therapeutic agents to enhance the sensitivity of chemo-resistant cancer cells to chemotherapy.
Authors
- Émilie Rigal
- Baptiste Legrand (ORCID: https://orcid.org/0000-0001-8931-7757)
- Guillaume Laconde (ORCID: https://orcid.org/0000-0001-5577-6111)
- Anthony R. Martin (ORCID: https://orcid.org/0000-0001-6187-6979)
- Lucile Bansard
- Sabine Gerbal‐Chaloin (ORCID: https://orcid.org/0000-0002-2549-7899)
- Jean‐Marc Pascussi (ORCID: https://orcid.org/0000-0002-5168-5383)
- William Bourguet (ORCID: https://orcid.org/0000-0002-0643-7719)
- Martine Daujat‐Chavanieu (ORCID: https://orcid.org/0000-0001-5560-1610)
- Tiphaine Huet (ORCID: https://orcid.org/0000-0002-8144-7917)
- Luc Brunel (ORCID: https://orcid.org/0009-0009-8446-1923)
- Alain Chavanieu (ORCID: https://orcid.org/0000-0002-0512-5115)
- Muriel Amblard (ORCID: https://orcid.org/0000-0001-8922-1755)
- Julie Pannequin (ORCID: https://orcid.org/0000-0002-9956-373X)
- V. Delfosse (ORCID: https://orcid.org/0000-0002-7436-7935)
- Margaux Ayeul (ORCID: https://orcid.org/0009-0004-4440-4936)
- Quentin Donati
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Institute for Regenerative Medicine & Biotherapy (FR)
- Centre de Biologie Structurale (FR)
- Institute for Neurosciences of Montpellier (FR)
- Institut des Biomolécules Max Mousseron (FR)
- Institut de Génomique Fonctionnelle (FR)
Publication Details
- Journal
- Oncogenesis
- Published
- 2025-08-30
- DOI
- https://doi.org/10.1038/s41389-025-00573-2
- Citations
- 3
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Groupement des Entreprises Françaises dans la lutte contre le Cancer