Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

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.

Phospholipid – Driven gene regulation

“…However, some headway has been made in identifying synthetic compounds that act upon SF‐1. In 2008, a number of inverse agonists for SF‐1 were identified [60–62]. Not only could these compounds inhibit SF‐1‐dependent gene transcription in luciferase assays, they also inhibited StAR expression in human adrenocortical cells [60], suggesting a possible therapeutic value in the treatment of adrenocortical cancers.…”

Therapeutic potential of Liver Receptor Homolog-1 modulators

“…One such molecule, RWJ101 was shown to be selective for LRH-1, however further work is being undertaken to improve its efficiency [94]. Recently an inverse agonist was identified for SF-1; 4-(heptyloxy)phenol (AC-45594) and its analogues were shown to regulate SF-1 activity and subsequently down regulate SF-1 target genes [109]. This molecule had no effect on LRH-1 activity indicating that despite their structural similarities, distinct ligands for LRH-1 and SF-1 could be synthesized.…”

Potent, Selective and Cell Penetrant Inhibitors of SF-1 by Functional Ultra-High-Throughput Screening

“…Compounds SID7969543 and SID7970631 were purchased from Life Chemicals (Kiev, Ukraine). Compound AC-45594 (Del Tredici et al, 2008) was acquired from Sigma-Aldrich (Milwaukee, WI).…”

“…5). An SF-1 inverse agonist recently described in the literature, AC-45594 (Del Tredici et al, 2008), was used as a positive control in the SF-1 experiment. Consistent with the screening results, SID7969543 and SID7970631 dose dependently inhibited lu- A, Gal4DBD_SF-1LBD activity is LBD-dependent.…”