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Identification of selective inverse agonists of the nuclear receptor SF‐1
Author(s) -
Tredici Andria Lee Del,
Andersen Carsten B,
Currier Erika A,
Lund Birgitte V,
Gauthier Natalie K,
Brann Mark R,
Olsson Roger,
Piu Fabrice
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a258-a
Subject(s) - nuclear receptor , receptor , estrogen receptor , steroidogenic factor 1 , inverse agonist , g protein coupled receptor , chemistry , hormone , estrogen related receptor gamma , microbiology and biotechnology , steroid , medicine , biology , endocrinology , pharmacology , gene , biochemistry , agonist , transcription factor , cancer , breast cancer
The nuclear receptor Steroidogenic Factor 1 (SF‐1, NR5A1) is essential to the development of adrenal and gonadal glands, as well as to sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. To date, no natural nor synthetic bona fide ligands have been identified, even though SF1 has been reported to associate with various phospholipids. A functional cell‐based assay to detect SF‐1 activity was developed using a proprietary R‐SAT TM platform technology. Levels of constitutive activity and signaling properties were thus examined. In a subsequent effort to identify ligands for the SF‐1 receptor, the screening of a small molecule library led to the discovery of several compounds with high affinity for SF‐1. These SF1 inverse agonists did not display any activity at other nuclear receptors, with the marked exception of weak agonism at both estrogen receptor subtypes. More importantly, the lead compound SF‐594 was able to inhibit dose‐dependently the expression of steroidogenic acute regulatory protein (StAR) in human adrenocortical cells, a well established SF‐1 target gene. Additional data will be presented.