At last, cancer-fighting inhibitors hit deubiquitinase target selectively

Abstract

In the body, ubiquitinating enzymes regulate proteins—marking them for disposal, for example—by adding ubiquitin peptides to them. And deubiquitinases (DUBs) refine regulation by removing ubiquitins. But DUBs can also promote tumor growth and curb anticancer immune responses. Researchers have been trying to find small molecules that fight cancer by inhibiting DUB activity, but progress has been slow. In two new studies, researchers have passed a milestone in the field by identifying some of the most promising inhibitors yet for USP7 (ubiquitin-specific protease-7), the most common anticancer target among the approximately 100 types of DUBs found in the body. USP7 can promote cancer by reducing levels of the tumor suppressor protein p53 and by impairing the immune system’s ability to detect and eliminate tumors. Inhibiting USP7 can have the opposite effect, killing cancer cells. However, previous inhibitors blocked USP7 essentially by only a single mechanism: bonding covalently or binding noncovalently to