RORγ antagonist 1 (compound 22), a potent betulinic acid derivative, is an antagonist of RORγ (K D =0.18 μM). RORγ antagonist 1 exhibits anti-proliferative activity in HPAF-II pancreatic cancer xenograft model. RORγ antagonist 1 inhibits RAS/MAPK and AKT/mTORC1 pathway, and induces caspase-dependent apoptosis in pancreatic cancer cells.