Transcriptional inhibition of the estrogen response element by antiestrogenic piperidinediones correlates with intercalation into DNA measured by energy calculations.

The energy of interaction of antiestrogenic ligands bound to DNA derived from molecular modeling was compared to the capacity of the ligands to directly inhibit the transcriptional activity of an estrogen responsive gene. 3-Phenylacetylamino-2,6-piperidinedione (A10) and related compounds were intercalated into a partially unwound DNA site in a canonical estrogen response element (ERE). The piperidinedione/ERE complexes were subjected to energy minimization and the strength of interaction of the ligands with the DNA was measured. The ability of the ligands to inhibit transactivation was assessed using a reporter gene constructed with the ERE of the vitellogenin gene promoter (ERE(v)-tk-Luc) transiently transfected into the human estrogen receptor-positive MCF-7 breast cancer cell line. The results demonstrate a direct correlation between the calculated energetic fit of the compounds in the ERE and inhibition of ERE(v) transactivation. The order of potency of the compounds to suppress estrogen-dependent reporter gene activity was identical to that previously shown for inhibiting the growth of MCF-7 cells. To our knowledge, these results provide the first direct experimental evidence that the predicted fit of a class of compounds into a defined DNA binding site correlates with the ability of the compounds to modulate specific gene functions regulated at that site.
AuthorsNeil Sidell, Prasong Tanmahasamut, Douglas E Ewing, Lawrence B Hendry
JournalThe Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 96 Issue 5 Pg. 335-45 (Sep 2005) ISSN: 0960-0760 [Print] England
PMID16054810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Estrogen Receptor Modulators
  • Intercalating Agents
  • Piperidines
  • DNA
  • Breast Neoplasms (drug therapy)
  • Cell Line, Tumor
  • Computer Simulation
  • DNA (metabolism)
  • Estrogen Receptor Modulators (pharmacology)
  • Female
  • Humans
  • Intercalating Agents (pharmacology)
  • Models, Molecular
  • Nucleic Acid Conformation
  • Piperidines (pharmacology)
  • Response Elements (physiology)
  • Thermodynamics
  • Transcription, Genetic (drug effects)

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