EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model

Sci Rep. 2019 Nov 21;9(1):17279. doi: 10.1038/s41598-019-53467-w.

Abstract

Uterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain or pressure, or infertility. Ovarian steroid hormones support the growth and maintenance of UFs. Ulipristal acetate (UPA) a selective progesterone receptor (PR) modulator (SPRM) reduce the size of UFs, inhibit ovulation and lead to amenorrhea. Recent liver toxicity concerns with UPA, diminished enthusiasm for its use and reinstate the critical need for a safe, efficacious SPRM to treat UFs. In the current study, we evaluated the efficacy of new SPRM, EC313, for the treatment for UFs using a NOD-SCID mouse model. EC313 treatment resulted in a dose-dependent reduction in the fibroid xenograft weight (p < 0.01). Estradiol (E2) induced proliferation was blocked significantly in EC313-treated xenograft fibroids (p < 0.0001). Uterine weight was reduced by EC313 treatment compared to UPA treatment. ER and PR were reduced in EC313-treated groups compared to controls (p < 0.001) and UPA treatments (p < 0.01). UF specific desmin and collagen were markedly reduced with EC313 treatment. The partial PR agonism and no signs of unopposed estrogenicity makes EC313 a candidate for the long-term treatment for UFs. Docking studies have provided a structure based explanation for the SPRM activity of EC313.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects*
  • Contraceptive Agents, Female / administration & dosage*
  • Contraceptive Agents, Female / adverse effects
  • Contraceptive Agents, Female / chemistry
  • Estrenes / administration & dosage
  • Estrenes / adverse effects
  • Female
  • Humans
  • Leiomyoma / drug therapy*
  • Leiomyoma / pathology
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Norpregnadienes / administration & dosage
  • Norpregnadienes / adverse effects
  • Oximes / administration & dosage
  • Oximes / adverse effects
  • Progesterone Congeners / administration & dosage*
  • Progesterone Congeners / adverse effects
  • Progesterone Congeners / chemistry
  • Receptors, Progesterone / agonists*
  • Receptors, Progesterone / chemistry
  • Receptors, Progesterone / metabolism
  • Structure-Activity Relationship
  • Uterine Neoplasms / drug therapy*
  • Uterine Neoplasms / pathology
  • Uterus / drug effects
  • Uterus / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Contraceptive Agents, Female
  • Estrenes
  • Norpregnadienes
  • Oximes
  • Progesterone Congeners
  • Receptors, Progesterone
  • selective progesterone receptor modulator EC313
  • asoprisnil
  • ulipristal acetate