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Identification of the first synthetic steroidogenic factor 1 inverse agonists : Pharmacological modulation of steroidogenic enzymes

Del Tredici, Andria L. ; Andersen, Carsten B. ; Currier, Erika A. ; Ohrmund, Steven R. ; Fairbain, Luke C. ; Lund, Birgitte W. ; Nash, Norman ; Olsson, Roger LU and Piu, Fabrice (2008) In Molecular Pharmacology 73(3). p.900-908
Abstract

Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological... (More)

Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological system of endocrine function, the expression of several reported SF-1 target genes, including SF-1 itself, was inhibited by treatment with AC-45594 and analogs. Thus, pharmacological modulation of SF-1 is critical to its function as an endocrine master regulator and has potentially important consequences to diseases in which SF-1 activity is critical.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Pharmacology
volume
73
issue
3
pages
9 pages
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • pmid:18055761
  • scopus:40849111661
ISSN
0026-895X
DOI
10.1124/mol.107.040089
language
English
LU publication?
no
id
42a5aef0-8e22-4317-85eb-c93ebe2126ec
date added to LUP
2019-10-02 10:23:57
date last changed
2020-08-26 05:02:19
@article{42a5aef0-8e22-4317-85eb-c93ebe2126ec,
  abstract     = {<p>Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological system of endocrine function, the expression of several reported SF-1 target genes, including SF-1 itself, was inhibited by treatment with AC-45594 and analogs. Thus, pharmacological modulation of SF-1 is critical to its function as an endocrine master regulator and has potentially important consequences to diseases in which SF-1 activity is critical.</p>},
  author       = {Del Tredici, Andria L. and Andersen, Carsten B. and Currier, Erika A. and Ohrmund, Steven R. and Fairbain, Luke C. and Lund, Birgitte W. and Nash, Norman and Olsson, Roger and Piu, Fabrice},
  issn         = {0026-895X},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {900--908},
  publisher    = {American Society for Pharmacology and Experimental Therapeutics},
  series       = {Molecular Pharmacology},
  title        = {Identification of the first synthetic steroidogenic factor 1 inverse agonists : Pharmacological modulation of steroidogenic enzymes},
  url          = {http://dx.doi.org/10.1124/mol.107.040089},
  doi          = {10.1124/mol.107.040089},
  volume       = {73},
  year         = {2008},
}