title: Detection and functional portrayal of a novel class of dihydrotestosterone derived selective progesterone receptor modulators (SPRM).
abstract: In early pregnancy, abortion can be induced by blocking the actions of progesterone receptors (PR). However, the PR antagonist, mifepristone (RU38486), is rather unselective in clinical use because it also cross-reacts with other nuclear receptors. Since the ligand-binding domain of human progesterone receptor (hPR) and androgen receptor (hAR) share 54% identity, we hypothesized that derivatives of dihydrotestosterone (DHT), the cognate ligand for hAR, might also regulate the hPR. Compounds designed and synthesized in our laboratory were investigated for their affinities for hPRB, hAR, glucocorticoid receptor (hGRα) and mineralocorticoid receptor (hMR), using whole cell receptor competitive binding assays. Agonistic and antagonistic activities were characterized by reporter assays. Nuclear translocation was monitored using cherry-hPRB and GFP-hAR chimeric receptors. Cytostatic properties and apoptosis were tested on breast cancer cells (MCF7, T-47D). One compound presented a favorable profile with an apparent neutral hPRB antagonistic function, a selective cherry-hPRB nuclear translocation and a cytostatic effect. 3D models of human PR and AR with this ligand were constructed to investigate the molecular basis of selectivity. Our data suggest that these novel DHT-derivatives provide suitable templates for the development of new selective steroidal hPR antagonists.
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: thomas.andrieu@dkf.unibe.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Andrieu
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: orlandomani@yahoo.de.
authors.forename: Orlando
authors.initials: O
authors.lastname: Mani
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: christine.goepfert@vetsuisse.unibe.ch.
authors.forename: Christine
authors.initials: C
authors.lastname: Goepfert
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: reto.bertolini@dkf.unibe.ch.
authors.forename: Reto
authors.initials: R
authors.lastname: Bertolini
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: andreas.guettinger@dkf.unibe.ch.
authors.forename: Andreas
authors.initials: A
authors.lastname: Guettinger
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: raschid.setoud@dkf.unibe.ch.
authors.forename: Raschid
authors.initials: R
authors.lastname: Setoud
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, USA. Electronic address: kuh@westernu.edu.
authors.forename: Kayla Y
authors.initials: KY
authors.lastname: Uh
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, USA. Electronic address: mbaker@ucsd.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Baker
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: felix.frey@sensemail.ch.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.affiliation: Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland; Department of Clinical Research, University of Berne, Berne, Switzerland. Electronic address: brigitte.frey@dkf.unibe.ch.
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Frey
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D013196:Dihydrotestosterone
keywords: Androgen derivative; Androgen receptor; MCF7; Progesterone receptor; T-47D