Endocrine Abstracts

Background: SF-1, an orphan nuclear receptor, controls adrenal organogenesis and is linked to both the pathogenesis and progression of ACC by multiple, independent genomic observations, including somatic amplification in ~90% of cases of pediatric ACC. The SF-1 ligand-binding domain contains a binding pocket that accepts small molecule transcriptional antagonists.

Objectives: Identify potent and drug-like SF-1 antagonists, investigate pharmacology in both isolated cell and whole animal systems, select a development candidate, and evaluate safety in rodent and non-rodent studies suitable for submission of an Investigational New Drug application.

Methods: Novel small molecules were synthesized and characterized for potency and selectivity as SF-1 antagonists in transcriptional and biochemical assays and as inhibitors of proliferation in the rat Leydig tumor cell line R2C and in short-term dissociated cultures of the pediatric ACC tumor SJ-ACC3. Anti-tumor activity was first confirmed in R2C cell-derived xenografts in nude mice and subsequently in two separate pediatric ACC xenografts.

Results: We surveyed several SF-1 expressing cell lines to characterize pharmacology. Only R2C responded by inhibition of proliferation. Structure-activity correlations between inhibition of SF-1 transcriptional activity and DNA synthesis in R2C cells or dissociated SJ-ACC3 tumor cells were robust. A metabolically stable SF-1 antagonist, OR-689, blocked growth of an R2C tumor at 60 and 100 mg/kg upon oral dosing. OR-449, a highly selective SF-1 antagonist, progressively inhibited R2C growth at 3, 10 and 30 mg/kg and at 30 mg/kg blocked SJ-ACC3 xenograft growth and partially inhibited a second pediatric tumor, SW1939. A responsive adult ACC PDX was not identified but significant changes in tumor biomarkers were observed. In 28-day safety studies in mouse and dog, OR-449 demonstrated no serious adverse events at 200 mg/kg. OR-449 (60 mg/kg in rat at day 14 and 200 mg/kg in dog at day 21) did not inhibit ACTH-induced glucocorticoid levels.

Discussion: OR-449 is a potential medical therapy for adult and pediatric ACC. The pharmacological activity of OR-449 is more readily observed in tumor models than in normal adrenal tissue in these studies.