8R81
Crystal structure of the hPXR-LBD in complex with compound JMV6845
Summary for 8R81
| Entry DOI | 10.2210/pdb8r81/pdb |
| Related | 8R82 |
| Descriptor | Nuclear receptor subfamily 1 group I member 2, ISOPROPYL ALCOHOL, 2,4,6-trimethyl-~{N}-[1-(phenylmethyl)benzimidazol-5-yl]benzenesulfonamide, ... (5 entities in total) |
| Functional Keywords | nuclear receptor, transcription factor, protac, xenobiotic receptor, gene regulation |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37305.17 |
| Authors | Delfosse, V.,Huet, T.,Bourguet, W. (deposition date: 2023-11-27, release date: 2025-06-11, Last modification date: 2025-09-17) |
| Primary citation | Bansard, L.,Laconde, G.,Delfosse, V.,Huet, T.,Ayeul, M.,Rigal, E.,Donati, Q.,Gerbal-Chaloin, S.,Daujat-Chavanieu, M.,Brunel, L.,Legrand, B.,Chavanieu, A.,Martin, A.R.,Pannequin, J.,Bourguet, W.,Amblard, M.,Pascussi, J.M. Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse. Oncogenesis, 14:34-34, 2025 Cited by PubMed Abstract: 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. PubMed: 40885723DOI: 10.1038/s41389-025-00573-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.45 Å) |
Structure validation
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