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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference:

Kayo Takamatsu1, Atsushi Takano, Nobumasa Yakushiji

  • 1Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.

Chemmedchem
|December 25, 2007
PubMed

Insights

Researchers developed novel Retinoid X receptor (RXR) agonists that are less lipophilic and selective for the RXR-alpha subtype. This finding may lead to more effective cancer treatments with fewer side effects.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Retinoid X receptor (RXR) agonists are potential cancer therapeutics, including for tamoxifen-resistant breast and taxol-resistant lung cancers.
  • Existing RXR agonists are highly lipophilic and lack subtype selectivity, limiting their therapeutic potential and increasing side effects.
  • RXR receptors have three subtypes (RXRalpha, RXRbeta, RXRgamma), and subtype-selective agonists are currently unknown.

Purpose of the Study:

  • To design and synthesize less-lipophilic and subtype-selective RXR agonists.
  • To investigate the relationship between lipophilicity and RXR subtype preference.

Main Methods:

  • Design and synthesis of novel sulfonamide-type RXR agonists.
  • Evaluation of RXR subtype selectivity (RXRalpha, RXRbeta, RXRgamma) for the synthesized compounds.

Main Results:

  • A novel sulfonamide-type RXR agonist, compound 8a, demonstrated preference for RXRalpha over RXRbeta and RXRgamma.
  • The potency of compound 8a was lower than that of known RXR pan-agonists.
  • Reducing lipophilicity in the hydrophobic interaction region of RXR agonists appears to enable subtype preference.

Conclusions:

  • The development of less-lipophilic, RXR-alpha-selective agonists is feasible.
  • Findings suggest a strategy for creating more potent and less-lipophilic subtype-selective RXR agonists.
  • This research could lead to cancer therapies with reduced undesirable side effects.

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