Our studies indicate that PRT543 selectively binds to PRMT5 and strongly inhibits its methyl-transferase activity at nanomolar concentrations, resulting in a significant dose-dependent anti-proliferative effect in two authenticated ACC cell lines and two ACC human organoid models, which was paralleled by downregulation of MYB, MYC and a panel of ACC-associated genes. Here, MYB is linked to adrenal cortex carcinoma.