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Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without

William H Catherino1, Minnie Malik, Paul Driggers

  • 1Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA. wcatherino@usuhs.mil

The Journal of Steroid Biochemistry and Molecular Biology
|May 25, 2010
PubMed

Insights

Novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947 show promise for uterine fibroid treatment. CP8947 effectively inhibited fibroid cell proliferation and reduced extracellular matrix production without affecting healthy uterine cells.

Area of Science:

  • Reproductive endocrinology and pharmacology.
  • Cell biology and molecular mechanisms of uterine fibroids.

Background:

  • Uterine leiomyomas (fibroids) are common, often symptomatic, with limited effective medical treatments.
  • There is a need for novel, selective, orally active therapies targeting fibroid growth and associated symptoms.

Purpose of the Study:

  • To evaluate the progesterone receptor (PR) specificity, activation, and in vivo effects of novel non-steroidal selective progesterone receptor modulators (SPRMs), CP8863 and CP8947.
  • To assess their impact on uterine leiomyoma cell proliferation and extracellular matrix (ECM) production.

Main Methods:

  • In vitro assays (alkaline phosphatase, ER-α expression) and in vivo McPhail assay for progestational activity.
  • Proliferation and gene expression studies in immortalized human leiomyoma and myometrial cells.
  • Assessment of selectivity for PR over ER-α, AR, and GR.

Main Results:

  • CP8863 and CP8947 demonstrated high selectivity for PR, not affecting ER-α, AR, or GR.
  • CP8947 showed progestational activity in rabbit endometrium and inhibited human leiomyoma cell proliferation at nanomolar concentrations.
  • CP8947 decreased ECM components (COL1A1, COL7A1) in leiomyoma cells without affecting myometrial cell proliferation.

Conclusions:

  • CP8947 is a potent, novel non-steroidal SPRM with PR selectivity.
  • It exhibits progestational activity, inhibits leiomyoma cell proliferation, and reduces ECM production.
  • CP8947 offers a potential targeted therapy for uterine fibroids without impacting normal myometrial cells.

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