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 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.
Footnotes
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ABBREVIATIONS: SF-1, steroidogenic factor-1; LBD, ligand binding domain; R-SAT, receptor selection and amplification technology; DMEM, Dulbecco's modified Eagle's medium; SFRE, SF-1 response element; DMSO, dimethyl sulfoxide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; bp, base pair(s); RT-PCR, reverse transcription-polymerase chain reaction; AC-45594, 4-(heptyloxy)phenol; LRH-1, liver receptor homolog-1; StAR, steroidogenic acute regulatory protein; HTS, high-throughput screening; ER, estrogen receptor; SFRE, SF-1 response element.
- Received July 16, 2007.
- Accepted November 28, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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