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Pharmacogenomics opportunities in nuclear receptor targeted cancer therapy

Matthieu Schapira1

  • 1Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. matthieu.schapira@med.nyu.edu

Current Cancer Drug Targets
|August 22, 2002
PubMed

Insights

Nuclear Hormone Receptors (NRs) are promising therapeutic targets for diseases like cancer. Understanding their structural mechanisms and genetic variations can lead to improved, personalized anti-cancer drug design.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Nuclear Hormone Receptors (NRs) are crucial transcription factors targeted by small molecule hormones.
  • Their structural properties make them ideal targets for therapeutic interventions, particularly in cancer treatment.
  • Existing anti-cancer drugs like tamoxifen and flutamide demonstrate the therapeutic potential of targeting NRs.

Purpose of the Study:

  • To explore the structural mechanisms of NR activation and inhibition by small molecule modulators.
  • To investigate the impact of nucleotide polymorphisms within NR Ligand Binding Domains (LBDs) on drug response.
  • To facilitate the rational design of novel, personalized anti-cancer therapies.

Main Methods:

  • Analysis of crystal structures of at least nine NR Ligand Binding Domains (LBDs).
  • Investigating the atomic-level interactions between NRs, agonists, antagonists, and co-regulators.
  • Mapping nucleotide polymorphisms onto LBD structures to understand altered ligand binding.

Main Results:

  • Structural insights reveal how agonists and antagonists modulate co-activator and co-repressor protein recruitment.
  • Nucleotide polymorphisms in NR LBDs can significantly alter or reverse receptor response to small molecule ligands.
  • Structural mapping of polymorphisms provides atomic models for drug resistance in cancer therapy.

Conclusions:

  • Detailed structural knowledge of NRs offers significant therapeutic opportunities.
  • Understanding polymorphism-mediated resistance is key to developing next-generation anti-cancer drugs.
  • Personalized drug design based on individual NR LBD variations holds promise for improved cancer treatment outcomes.

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