Identification and characterization of steroidogenic factor-1 inverse agonists.
The transcription factor Steroidogenic Factor-1 (Ad4BP/SF-1; NR5A1 according to the standard nomenclature) has an essential role in adrenogonadal development. Furthermore, SF-1 is amplified and overexpressed in most cases of adrenocortical tumor occurring in children; studies performed in transgenic mice have shown that an increased SF-1 dosage triggers tumor formation in the adrenal cortex. For these reasons, drugs interfering with SF-1 action would represent a promising tool to be added to the current pharmacological protocols in the therapy of adrenocortical cancer. Here, we describe the methods how isoquinolinone compounds inhibiting the constitutive transcriptional activity of SF-1 (SF-1 inverse agonists) were identified and characterized. These compounds have the attributes to inhibit the increase in proliferation triggered by an augmented SF-1 dosage in adrenocortical tumor cells and to reduce their steroid production. This latter property may also reveal beneficial for drugs used in the therapy of adrenocortical tumors to alleviate symptoms of virilization and Cushing often associated with tumor burden.
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, Université de Nice Sophia Antipolis, Valbonne, France.
Mabrouka
M
Doghman
Franck
F
Madoux
Peter
P
Hodder
Enzo
E
Lalli
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000819:agonists* / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054314:Drug Inverse Agonism; D006801:Humans; D007546:Isoquinolines / Q000819:agonists* / Q000737:chemistry* / Q000494:pharmacology; D054339:Steroidogenic Factor 1 / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection / Q000379:methods
D000970:Antineoplastic Agents; D007546:Isoquinolines; D054339:Steroidogenic Factor 1; D013256:Steroids