8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

Irene O. Aninye, Kenneth C. Berg, Andy R. Mollo, Steven K. Nordeen, Elizabeth M. Wilson, David J. Shapiro

Research output: Contribution to journalArticlepeer-review


The progesterone receptor (PR) plays a key role in reproduction and is important in cancers of the reproductive tract. Current PR antagonists usually compete for progestin binding in the PR ligand-binding pocket and often exhibit cross-binding with other members of the steroid receptor family. Using stably transfected cells expressing reporter genes, a set of ∼150 theophylline analogues were screened for their ability to inhibit progesterone, estrogen, glucocorticoid and androgen signaling. The structure-activity studies presented here identify branched 8-alkylthio-6-thio-substitutions of theophylline as selective PR inhibitors. 6-Thio-8-(2-ethylbutyl)thiotheophylline (51), the most extensively studied derivative, does not act by competing with progestins for binding in the ligand-binding pocket of PR. It demonstrated the ability to inhibit the mouse mammary tumor virus (MMTV)-luciferase reporter and endogenous PR-regulated alkaline phosphatase activity in T47D breast cancer cells. Compound 51 is the lead member of a novel class of PR inhibitors that act outside the PR ligand-binding pocket, thus serving as a novel probe to investigate PR action and a lead for further development.

Original languageEnglish (US)
Pages (from-to)596-601
Number of pages6
Issue number6
StatePublished - May 2012


  • Progesterone
  • Small molecule inhibitor
  • Steroid receptor
  • Structure activity relationship
  • Theophylline analogue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry


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