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

ABSTRACT: Pregnane X receptor (PXR) is a ligand-activated transcription factor that binds diverse compounds and upregulates drug metabolism machinery in response. PXR activation is detrimental to drug efficacy and safety because it reduces active drug concentrations and increases reactive metabolites, leading to toxicity and/or drug-drug interactions. Thus, effort must be expended in drug development pipelines to assess PXR activation by lead candidates and chemically modify agonists to reduce PXR liabilities while maintaining on-target potencies. Coadministration of drugs with PXR antagonists could prevent PXR-mediated metabolism events, but such compounds are rare and may themselves be converted to agonists by metabolic enzymes or PXR mutations. Here, we report the design, synthesis, optimization,

SUBMITTER: Huber AD 

PROVIDER: S-EPMC11584202 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature