Discovery of a small molecular compound simultaneously targeting RXR and HADC: design, synthesis, molecular docking and bioassay

Bioorg Med Chem Lett. 2013 Jul 1;23(13):3891-5. doi: 10.1016/j.bmcl.2013.04.067. Epub 2013 May 7.

Abstract

Retinoid X receptor (RXR) and Histone deacetylase (HDAC) are considered important targets for anti-cancer therapy due to their crucial roles in genetic or epigenetic regulations of cancer development and progression. Here, we have designed and synthesized a novel compound which targets both RXR and HADC. This dual-targeting agent is derived from bexarotene and suberoylanilide hydroxamic acid (SAHA), prototypical RXR agonist and HDAC inhibitor, respectively. Molecular docking studies demonstrate that this agent has a relatively strong affinity to RXR and HADC. Importantly, it presents the potentials of activation of RXR and inhibition of HDAC in both cell-free and whole-cell assays, and displays anti-proliferative effect on representative cancer cell lines and drug-resistant cancer cell lines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • HL-60 Cells
  • HeLa Cells
  • Histone Deacetylases / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Retinoid X Receptors / agonists*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Retinoid X Receptors
  • Small Molecule Libraries
  • Histone Deacetylases