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

Autor:	Huber AD; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Jung YH; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Li Y; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Lin W; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Wu J; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Poudel S; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Carrigan AG; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States., Mishra A; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States., High AA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States., Chen T; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 1000, Memphis, Tennessee 38105-3678, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Oct 24; Vol. 67 (20), pp. 18549-18575. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1021/acs.jmedchem.4c01926
Abstrakt:	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, and biological validation of proteolysis targeting chimeras that induce PXR degradation through E3 ubiquitin ligase recruitment. PXR degradation blocks agonist-induced gene expression and enhances anticancer effects of the chemotherapy paclitaxel, a known PXR agonist and substrate of downstream metabolic enzymes.
Databáze:	MEDLINE
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