MON-LB-Late-Breaking Poster Session 3
Bench to Bedside
Expo Halls ABC (Moscone Center)
Poster Board MON-LB-02
SF-1 (steroidogenic factor-1) is a major transcription factor for steroidogenic gene expression in the adrenal gland. An SF-1 antagonist could have clinical value in management of Cushing’s syndrome. We identified more potent and stable SF-1 antagonists than previously published (1,2) and investigated inhibition of steroid synthesis in cultured adrenocortical cells. The antagonists OR-559 and OR-907 not only suppress gene transcription through the SF-1 ligand-binding domain (LBD) EC50 (0.04-0.1 µM), they also induce release of co-activator peptides derived from DAX-1 and PGC-1a from the SF-1 LBD. These studies confirmed direct and functional interaction of the SF-1 LBD with transcriptionally active antagonists. The most potent of these, OR-907, suppressed cortisol secretion by ~85% in the H295R adrenocortical cancer cell line, and in human and monkey primary adrenal cultures, in a dose-responsive manner. SF-1 antagonists appear to inhibit cortisol (or corticosterone) synthesis at two separate steps. First, in H295R cells, OR-907 blocks the synthesis of pregnenolone from cholesterol, as determined by LC-MS, but does not block the conversion of exogenous 22-OH-cholesterol, suggesting that inhibition takes place upstream of Cyp11A1. Second, in H295R cells and primary rat adrenal cells, Cyp21A2 mRNA is suppressed. OR-559 also blocks the conversion of progesterone to deoxycorticosterone in primary rat adrenal cells, consistent with suppression of Cyp21 activity. In comparison to clinically-useful inhibitors of adrenal steroidogenesis, such as metyrapone, the mechanism of action of SF-1 antagonists in culture suggests that buildup of precursor steroids or diversion of precursors to adrenal androgens during treatment of Cushing’s syndrome could be significantly reduced.
(1) Madoux et al., Mol Pharmacol 2008; 73:1776. (2) Roth et al. Bioorg Med Chem Lett 2008; 18:2628.
Disclosure: PDC: Employee, Orphagen Pharmaceuticals. JM: Employee, Orphagen Pharmaceuticals. HT: Employee, Orphagen Pharmaceuticals. RS: Consultant, Orphagen Pharmaceuticals. RJA: Scientific Board Member, Orphagen Pharmaceuticals. SMT: Chief Scientific Officer, Orphagen Pharmaceuticals.
*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm
Sources of Research Support:
Orphagen Pharmaceuticals and NCI Phase 1 SBIR Grant CA099875 awarded to S. Thacher