Orally active aminosteroid RM-581 suppresses tumor growth and metastasis formation in a gemcitabine-resistant orthotopic xenograft pancreatic cancer model

New agents with distinct mechanisms of action are urgently needed to overcome drug resistance and improve survival, particularly in highly lethal cancers. The estrane derivative RM-581, designed through structure–activity relationship studies, needed to demonstrate efficacy in poor-prognosis cancer models, such as pancreatic cancer, to validate its therapeutic potential. Oral administration of RM-581 (30 mg/kg) in female mice revealed improved pharmacokinetic parameters (C max , AUC, bioavailability) when formulated in Propylene glycol: DMSO, compared with Glycerol: DMSO. Plasma levels of RM-581 increased dose-dependently, and once-daily dosing produced exposure comparable to twice-daily administration. In an orthotopic PANC-1 human pancreatic cancer xenograft model with female nu/nu mice, orally administered RM-581 inhibited tumor growth in a dose-dependent manner by 11%, 54%, and 74% at 10, 40 and 80 mg/kg, respectively. RM-581 at 80 mg/kg suppressed tumor growth by 74–95% and prevented metastasis, whereas 33% of control mice developed metastatic lesions. The combination of RM-581 with Pravastatin also prevented metastasis. RM-581 was well tolerated during 35- and 48-day treatment periods, with no clinical signs of toxicity, including stable body weight, normal organ appearance, unremarkable histopathology, and normal animal behavior, indicating a favorable safety profile. Together, these findings position RM-581 as a promising preclinical candidate warranting advancement into clinical development.