OR-449

OR-449 is a first-in-class, potent, selective, and orally bioavailable small molecule antagonist of steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor and transcription factor essential for adrenal gland growth and development. Developed by Orphagen Pharmaceuticals using proprietary screening technology, OR-449 potently inhibits SF-1 transcriptional activity (IC50 = 15-20 nM) and demonstrates striking anti-proliferative effects in SF-1-expressing tumor models, including >90% inhibition of DNA synthesis in rat Leydig tumor R2C cells (IC50 = 68 nM) and complete tumor growth inhibition in R2C xenografts and pediatric ACC patient-derived xenografts (SJ-ACC3) at oral doses of 30 mg/kg daily. It regulates malignant steroid profiles and SF-1-responsive genes in ACC models while showing no serious adverse effects in rodent and non-rodent safety studies up to 200 mg/kg, positioning it as a targeted therapy for adrenocortical carcinoma (ACC) and malignant Leydig cell tumors (LCTs).[1][2][7][12]