First-in-Class\nSmall Molecule Degrader of Pregnane\nX Receptor Enhances Chemotherapy Efficacy

Pregnane X receptor (PXR) is a ligand-activated transcription\nfactor\nthat binds diverse compounds and upregulates drug metabolism machinery\nin response. PXR activation is detrimental to drug efficacy and safety\nbecause it reduces active drug concentrations and increases reactive\nmetabolites, leading to toxicity and/or drug–drug interactions.\nThus, effort must be expended in drug development pipelines to assess\nPXR activation by lead candidates and chemically modify agonists to\nreduce PXR liabilities while maintaining on-target potencies. Coadministration\nof drugs with PXR antagonists could prevent PXR-mediated metabolism\nevents, but such compounds are rare and may themselves be converted\nto agonists by metabolic enzymes or PXR mutations. Here, we report\nthe design, synthesis, optimization, and biological validation of\nproteolysis targeting chimeras that induce PXR degradation through\nE3 ubiquitin ligase recruitment. PXR degradation blocks agonist-induced\ngene expression and enhances anticancer effects of the chemotherapy\npaclitaxel, a known PXR agonist and substrate of downstream metabolic\nenzymes.