In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation

Madhukumar Venkatesh, Hongwei Wang, Julie Cayer, Melissa Leroux, Dany Salvail, Bhaskar Das, Jay E. Wrobel, Sridhar Mani

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The pregnane X receptor (PXR) is a master regulator of xenobiotic clearance and is implicated in deleterious drug interactions (e.g., acetaminophen hepatotoxicity) and cancer drug resistance. However, small-molecule targeting of this receptor has been difficult; to date, directed synthesis of a relatively specific PXR inhibitor has remained elusive. Here we report the development and characterization of a first-in-class novel azole analog [1-(4-(4-(((2R,4S)-2-(2, 4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl) ethanone (FLB-12)] that antagonizes the activated state of PXR with limited effects on other related nuclear receptors (i.e., liver X receptor, farnesoid X receptor, estrogen receptor α, peroxisome proliferator-activated receptor γ, and mouse constitutive androstane receptor). We investigated the toxicity and PXR antagonist effect of FLB-12 in vivo. Compared with ketoconazole, a prototypical PXR antagonist, FLB-12 is significantly less toxic to hepatocytes. FLB-12 significantly inhibits the PXR-activated loss of righting reflex to 2,2,2-tribromoethanol (Avertin) in vivo, abrogates PXR-mediated resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in colon cancer cells in vitro, and attenuates PXR-mediated acetaminophen hepatotoxicity in vivo. Thus, relatively selective targeting of PXR by antagonists is feasible and warrants further investigation. This class of agents is suitable for development as chemical probes of PXR function as well as potential PXRdirected therapeutics.

Original languageEnglish (US)
Pages (from-to)124-135
Number of pages12
JournalMolecular Pharmacology
Volume80
Issue number1
DOIs
StatePublished - Jul 2011

Fingerprint

Azoles
irinotecan
Acetaminophen
In Vitro Techniques
pregnane X receptor
Righting Reflex
Peroxisome Proliferator-Activated Receptors
Ketoconazole
Poisons
Xenobiotics
Cytoplasmic and Nuclear Receptors
Drug Interactions
Drug Resistance
Estrogen Receptors
Colonic Neoplasms
Hepatocytes

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation. / Venkatesh, Madhukumar; Wang, Hongwei; Cayer, Julie; Leroux, Melissa; Salvail, Dany; Das, Bhaskar; Wrobel, Jay E.; Mani, Sridhar.

In: Molecular Pharmacology, Vol. 80, No. 1, 07.2011, p. 124-135.

Research output: Contribution to journalArticle

Venkatesh, Madhukumar ; Wang, Hongwei ; Cayer, Julie ; Leroux, Melissa ; Salvail, Dany ; Das, Bhaskar ; Wrobel, Jay E. ; Mani, Sridhar. / In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation. In: Molecular Pharmacology. 2011 ; Vol. 80, No. 1. pp. 124-135.
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