Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

Arunima Biswas; Sridhar Mani; Matthew R Redinbo; Matthew D Krasowski; Hao Li; Sean Ekins

doi:10.1007/s11095-009-9901-7

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Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

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Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

Arunima Biswas, Sridhar Mani, Matthew R Redinbo, Matthew D Krasowski, Hao Li and Sean Ekins

Pharmaceutical research, Vol.26(8), pp.1807-1815

08/2009

DOI: 10.1007/s11095-009-9901-7

PMCID: PMC2846309

PMID: 19415465

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Abstract

The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics.

Agonists

Antagonists

Pregnane X Receptor

Machine Learning

Pharmacophore

Details

Title: Subtitle: Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists
Creators: Arunima Biswas - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461
Sridhar Mani - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461
Matthew R Redinbo - Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
Matthew D Krasowski - Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
Hao Li - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461
Sean Ekins - Collaborations in Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046, U.S.A
Resource Type: Journal article
Publication Details: Pharmaceutical research, Vol.26(8), pp.1807-1815
DOI: 10.1007/s11095-009-9901-7
PMID: 19415465
PMCID: PMC2846309
NLM abbreviation: Pharm Res
ISSN: 0724-8741
eISSN: 1573-904X
Language: English
Date published: 08/2009
Academic Unit: Pathology
Record Identifier: 9984047849902771

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