title: Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA. wcatherino@usuhs.mil
authors.forename: William H
authors.initials: WH
authors.lastname: Catherino
authors.forename: Minnie
authors.initials: M
authors.lastname: Malik
authors.forename: Paul
authors.initials: P
authors.lastname: Driggers
authors.forename: Scott
authors.initials: S
authors.lastname: Chappel
authors.forename: James
authors.initials: J
authors.lastname: Segars
authors.forename: Joseph
authors.initials: J
authors.lastname: Davis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004717:Endometrium / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007889:Leiomyoma / Q000188:drug therapy*; D009215:Myometrium / Q000187:drug effects; D011817:Rabbits; D011980:Receptors, Progesterone / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; C553181:CP 8947; C465309:CP8863; D007211:Indoles; D011980:Receptors, Progesterone