Because ACC is an orphan disease and no new drugs have been approved for more than five decades, we performed large scale drug screening in ACC preclinical models and identified TAK-243, a first-in-class ubiquitin-activating enzyme E1 inhibitor, as a potent agent active at nanomolar concentrations by itself and synergistic with the current treatments of ACC. The gene discussed is UBA1; the disease is adrenal cortex carcinoma.