First-in-Class Small Molecule Degrader of Pregnane X Receptor Enhances Chemotherapy Efficacy

Area of Science:

• Pharmacology
• Molecular Biology
• Drug Development

Background:

• Pregnane X receptor (PXR) is a transcription factor that regulates drug metabolism.
• PXR activation can reduce drug efficacy and increase toxicity by altering drug concentrations and generating reactive metabolites.
• Current strategies to manage PXR liabilities, such as antagonists, have limitations.

Purpose of the Study:

• To design and validate novel proteolysis targeting chimeras (PROTACs) for inducing PXR degradation.
• To evaluate the efficacy of PXR degradation in blocking PXR-mediated gene expression.
• To assess the impact of PXR degradation on the anticancer effects of paclitaxel.

Main Methods:

• Design, synthesis, and optimization of PXR-targeting PROTACs.
• Biological validation of PROTACs in cellular and/or in vivo models.
• Assessment of PXR target gene expression and paclitaxel efficacy.

Main Results:

• Successfully developed and optimized PROTACs that induce PXR degradation via E3 ubiquitin ligase recruitment.
• Demonstrated that PXR degradation effectively blocks agonist-induced PXR target gene expression.
• Showed that PXR degradation enhances the anticancer effects of paclitaxel, a known PXR substrate.

Conclusions:

• Proteolysis targeting chimeras represent a promising strategy for eliminating PXR liabilities in drug development.
• Targeting PXR for degradation offers a novel therapeutic approach to improve drug safety and efficacy, particularly for chemotherapy agents.
• This work provides a new tool to overcome challenges associated with PXR-mediated drug metabolism and drug-drug interactions.