Targeting Pregnane X Receptor with a Potent Agonist-Based PROTAC to Delay Colon Cancer Relapse

Bansard, L.; Laconde, G.; Delfosse, V.; Huet, T.; Ayeul, M.; Rigal, E.; Donati, Q.; Gerbal-Chaloin, S.; Daujat-Chavanieu, M.; Legrand, B.; Chavanieu, A.; Pannequin, J.; Bourguet, W.; Amblard, M.; Pascussi, J.-M.

doi:10.1101/2024.06.18.599474

bioRxiv · 10.1101/2024.06.18.599474

Targeting Pregnane X Receptor with a Potent Agonist-Based PROTAC to Delay Colon Cancer Relapse

Bansard, L.·Laconde, G.·Delfosse, V.·Huet, T.·Ayeul, M.·Rigal, E.·Donati, Q.·Gerbal-Chaloin, S.·Daujat-Chavanieu, M.·Legrand, B.·Chavanieu, A.·Pannequin, J.·Bourguet, W.·Amblard, M.·Pascussi, J.-M.

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Abstract

Tumor recurrence is often attributed to drug-tolerant cancer stem cells. We previously demonstrated that down regulation of the Pregnane X Receptor (PXR, NR1I2) decreases chemoresistance of cancer stem cells and prevents colorectal cancer recurrence in xenograft mouse models. These is a lack of PXR antagonists that are appropriate for clinical use. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) that induces polyubiquitination and degradation of human PXR protein in an E3 CRBN ubiquitin ligase- and the 26S proteasome-dependent manner. This molecule specifically degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, but not in primary cultures of human hepatocytes. Crucially, JMV7048 decreased PXR protein expression in colon cancer stem cells and sensitized them to chemotherapy significantly delaying cancer relapse in vivo. PROTACs targeting PXR protein could thus become novel therapeutic agents to enhance cancer cell sensitivity to chemotherapy.

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Bansard, L., Laconde, G., Delfosse, V., Huet, T., Ayeul, M., Rigal, E., Donati, Q., Gerbal-Chaloin, S., Daujat-Chavanieu, M., Legrand, B., Chavanieu, A., Pannequin, J., Bourguet, W., Amblard, M., Pascussi, J.-M.. 2024-06-22. Targeting Pregnane X Receptor with a Potent Agonist-Based PROTAC to Delay Colon Cancer Relapse. https://doi.org/10.1101/2024.06.18.599474

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