Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Tumor recurrence is often linked to drug-tolerant cancer cells.
• Downregulation of Pregnane X Receptor (PXR) reduces chemoresistance and prevents recurrence.
• There is a need for clinically viable PXR antagonists.

Purpose of the Study:

• To design and synthesize a novel PXR antagonist using a PROTAC approach.
• To evaluate the efficacy of the PROTAC in degrading PXR and sensitizing cancer cells to chemotherapy.

Main Methods:

• Design and synthesis of a PXR agonist-based PROTAC (JMV7048).
• Assessment of PXR degradation via ubiquitination and proteasome pathways.
• Evaluation of JMV7048's effect on cancer cell lines (colon carcinoma, hepatoma, pancreatic cancer) and primary human hepatocytes.
• Testing in xenograft mouse models to assess chemoresistance and recurrence prevention.

Main Results:

• JMV7048 effectively promotes polyubiquitination and degradation of human PXR protein.
• Selective PXR degradation observed in various cancer cell lines, sparing primary hepatocytes.
• Reduced PXR expression in drug-tolerant colon cancer cells sensitized them to chemotherapy.
• Significant delay in cancer relapse observed in xenograft models.

Conclusions:

• PXR-targeting PROTACs, like JMV7048, represent a promising therapeutic strategy.
• This approach can enhance the sensitivity of chemo-resistant cancers to chemotherapy.
• PROTACs offer a novel avenue for preventing tumor recurrence.