Detection and functional portrayal of a novel class of dihydrotestosterone derived selective progesterone receptor modulators (SPRM)

Thomas Andrieu; Orlando Mani; Christine Goepfert; Reto Bertolini; Andreas Guettinger; Raschid Setoud; Kayla Y Uh; Michael E Baker; Felix J Frey; Brigitte M Frey

doi:10.1016/j.jsbmb.2014.12.009

Detection and functional portrayal of a novel class of dihydrotestosterone derived selective progesterone receptor modulators (SPRM)

J Steroid Biochem Mol Biol. 2015 Mar:147:111-23. doi: 10.1016/j.jsbmb.2014.12.009. Epub 2014 Dec 23.

Authors

Affiliations

¹ Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: thomas.andrieu@dkf.unibe.ch.
² Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: orlandomani@yahoo.de.
³ Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: christine.goepfert@vetsuisse.unibe.ch.
⁴ Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: reto.bertolini@dkf.unibe.ch.
⁵ Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: andreas.guettinger@dkf.unibe.ch.
⁶ Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: raschid.setoud@dkf.unibe.ch.
⁷ Department of Medicine, University of California, San Diego, La Jolla, USA. Electronic address: kuh@westernu.edu.
⁸ Department of Medicine, University of California, San Diego, La Jolla, USA. Electronic address: mbaker@ucsd.edu.
⁹ Department of Nephrology and Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland. Electronic address: felix.frey@sensemail.ch.
¹⁰ 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.

PMID: 25541437
DOI: 10.1016/j.jsbmb.2014.12.009

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.

Keywords: Androgen derivative; Androgen receptor; MCF7; Progesterone receptor; T-47D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Breast Neoplasms / drug therapy
Breast Neoplasms / metabolism
Cell Line
Cell Line, Tumor
Dihydrotestosterone / analogs & derivatives*
Dihydrotestosterone / pharmacology*
Female
Humans
Models, Molecular
Protein Binding
Receptors, Androgen / metabolism
Receptors, Glucocorticoid / metabolism
Receptors, Mineralocorticoid / metabolism
Receptors, Progesterone / antagonists & inhibitors*
Receptors, Progesterone / metabolism*
Transcription, Genetic / drug effects

Substances

Receptors, Androgen
Receptors, Glucocorticoid
Receptors, Mineralocorticoid
Receptors, Progesterone
Dihydrotestosterone