title: Novel progesterone receptor modulators with gene selective and context-dependent partial agonism.
abstract: Progesterone receptor (PR) modulators are used in contraception and post-menopausal hormone therapy, and are under clinical development for reproductive disorders such as uterine fibroids and endometriosis. Development of tissue selective PR modulators (SPRMs) with reduced side effects and improved pharmacology represents a large unmet medical need in the area of women's health. One approach to addressing this need is to focus on the two PR isoforms PR-A and PR-B. In vitro and in vivo studies have revealed both distinct as well as overlapping gene regulation and functional responses of the two PR isoforms that suggests that PR-A selective modulators may retain a desired biological profile. We have identified a chemical series of 4-(4-chlorophenyl)-substituted piperazine carbimidothioic acid esters (PCEs) that have partial PR agonist activity and selectively activate some PR-A isoform regulated genes in T47D cells. However, full microarray analysis in these cells does not predict a global isoform selective profile for these compounds, but rather a unique gene-selective profile is observed relative to steroidal progestins. Using multiplexed peptide interaction profiling and co-activator recruitment assays we find that the mechanism of partial agonism is only partly defined by the ability to recruit known co-activators or peptides but also depends on the cell and promoter context of the gene under investigation. The data demonstrate global consequences of mechanistic and functional differences that can lead to selective biological responses of novel steroid receptor modulators.
authors.affiliation: Women's Health & Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19101-2528, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Berrodin
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jelinsky
authors.forename: Nilsa
authors.initials: N
authors.lastname: Graciani
authors.forename: John A
authors.initials: JA
authors.lastname: Butera
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Yudt
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003271:Contraceptive Agents, Female / Q000009:adverse effects / Q000627:therapeutic use; D004715:Endometriosis / Q000188:drug therapy; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011372:Progestins / Q000009:adverse effects / Q000627:therapeutic use; D011980:Receptors, Progesterone / Q000819:agonists* / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D059002:Androgen Receptor Antagonists; D003271:Contraceptive Agents, Female; D010879:Piperazines; D011372:Progestins; D011980:Receptors, Progesterone; D017258:Medroxyprogesterone Acetate