Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium

William H. Catherino, Minnie Malik, Paul Driggers, Scott Chappel, James Segars, Joseph Davis

Research output: Contribution to journalArticlepeer-review

Abstract

Uterine leiomyomas are highly prevalent and often symptomatic, but current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. The goal of these studies was to determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on leiomyoma cell proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947. In vitro progestational activity was assessed by alkaline phosphatase assay and ER-α expression. In vivo progestational activity was assayed by the McPhail assay. Proliferation and gene expression studies were performed in immortalized human leiomyoma and myometrial cells. Both CP8863 and CP8947 were highly selective for progesterone receptor (PR) but not for ER-α, AR, and GR. Both compounds induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-α in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium. Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. Extracellular matrix components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. CP8947 was a potent novel non-steroidal SPRM that was selective for PR, demonstrated progestational activity in endometrium, inhibited leiomyoma cell proliferation and decreased ECM component production, without disrupting myometrial cell proliferation.

Original languageEnglish (US)
Pages (from-to)279-286
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume122
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • Apoptosis
  • Endometrium
  • Extracellular matrix
  • Leiomyoma
  • Myometrium
  • Selective progesterone receptor modulator

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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