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 and, 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 (compound 3, FLB-12) that antagonizes the activated state of PXR with limited effects on other related nuclear receptors (i.e., LXR, FXR, ERα, PPARγ and mCAR). We investigated the toxicity and PXR antagonist effect of compound 3 in vivo. When compared with ketoconazole, a prototypical PXR antagonist, compound 3 is significantly less toxic to hepatocytes. Compound 3 significantly inhibits the PXR-activated loss of righting reflex to avertin in vivo, abrogates PXR-mediated resistance to 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 PXR-directed therapeutics.
- Received February 14, 2011.
- Revision received March 22, 2011.
- Accepted March 23, 2011.
- The American Society for Pharmacology and Experimental Therapeutics