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Pharmaceutical Research

, Volume 26, Issue 8, pp 1807–1815 | Cite as

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

  • Arunima Biswas
  • Sridhar ManiEmail author
  • Matthew R. Redinbo
  • Matthew D. Krasowski
  • Hao Li
  • Sean Ekins
Expert Review

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.

KEY WORDS

agonists antagonists machine learning pharmacophore pregnane X receptor 

Notes

Acknowledgment

The authors would like to gratefully acknowledge the many collaborators involved in the PXR agonist and antagonist research to date including: Dr’s. Ni Ai, Vladyslav Kholodovych and William J Welsh, (Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey), Dr Sandhya Kortagere (Drexel University), Dr. Michael Sinz (Bristol Myers Squibb), Dr Erica Reschly (University of Pittsburgh School of Medicine), Dr. Peter W. Swaan (University of Maryland), Dr. Cheng Chang (Pfizer), Dr. Akash Khandelwal, Dr. Erin Schuetz (St. Jude Childrens Research Hospital) and Dr. Kenneth Bachmann.

Supplementary material

11095_2009_9901_MOESM1_ESM.doc (32 kb)
Supplementary Table 1 (DOC 31.5 KB)
11095_2009_9901_MOESM2_ESM.doc (63 kb)
Supplementary Table 2 (DOC 63.0 KB)

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Arunima Biswas
    • 1
  • Sridhar Mani
    • 1
    Email author
  • Matthew R. Redinbo
    • 2
  • Matthew D. Krasowski
    • 3
  • Hao Li
    • 1
  • Sean Ekins
    • 4
    • 5
    • 6
    • 7
  1. 1.Albert Einstein Cancer CenterAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of ChemistryUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Department of PathologyUniversity of PittsburghPittsburghUSA
  4. 4.Collaborations in ChemistryJenkintownUSA
  5. 5.Collaborative Drug Discovery Inc.,BurlingameUSA
  6. 6.Department of Pharmaceutical SciencesUniversity of MarylandCollege ParkUSA
  7. 7.Department of PharmacologyUniversity of Medicine & Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical SchoolPiscatawayUSA

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