Identification of the first synthetic steroidogenic factor 1 inverse agonists: pharmacological modulation of steroidogenic enzymes.
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.
ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, San Diego, CA 92121, USA.
Andria L
AL
Del Tredici
Carsten B
CB
Andersen
Erika A
EA
Currier
Steven R
SR
Ohrmund
Luke C
LC
Fairbain
Birgitte W
BW
Lund
Norman
N
Nash
Roger
R
Olsson
Fabrice
F
Piu
D000310:Adrenal Gland Neoplasms / Q000473:pathology; D000818:Animals; D002277:Carcinoma / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D010636:Phenols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000819:agonists* / Q000138:chemical synthesis* / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C527833:4-(heptyloxy)phenol; D008024:Ligands; D010636:Phenols; D012333:RNA, Messenger; D054339:Steroidogenic Factor 1; D000242:Cyclic AMP; D008156:Luciferases; D002786:Cholesterol Side-Chain Cleavage Enzyme