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

Andrieu, Thomas; Mani, Orlando; Göpfert, Christine; Bertolini, Reto; Güttinger, Andreas; Setoud, Raschid; Uh, Kayla Y; Baker, Michael E; Frey, Felix J; Frey, Brigitte M (2015). Detection and functional portrayal of a novel class of dihydrotestosterone derived selective progesterone receptor modulators (SPRM). Journal of steroid biochemistry and molecular biology, 147, pp. 111-123. Elsevier 10.1016/j.jsbmb.2014.12.009

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
08 Faculty of Science > Department of Biology > Institute of Cell Biology

UniBE Contributor:

Andrieu, Thomas; Mani, Orlando; Göpfert, Christine; Bertolini, Reto; Güttinger, Andreas; Setoud, Raschid and Frey, Brigitte

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
600 Technology > 630 Agriculture

ISSN:

0960-0760

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Gautschi-Steffen

Date Deposited:

02 Apr 2015 13:31

Last Modified:

15 Oct 2015 10:51

Publisher DOI:

10.1016/j.jsbmb.2014.12.009

PubMed ID:

25541437

Uncontrolled Keywords:

Androgen derivative, Androgen receptor, MCF7, Progesterone receptor, T-47D

BORIS DOI:

10.7892/boris.66457

URI:

https://boris.unibe.ch/id/eprint/66457

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