ADVERTISEMENT
2 /3 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Pharmaceuticals

At last, cancer-fighting inhibitors hit deubiquitinase target selectively

Two research groups find small molecules that block the enzyme USP7 and show promise in mice with tumors

by Stu Borman
October 19, 2017 | APPEARED IN VOLUME 95, ISSUE 42

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.

[+]Enlarge
Credit: Nature
Genentech crystal structure of GNE-6776 (stick structure, top center) bound to USP7 (active site of which is ball-and-stick structure, bottom right).
Credit: Nature
Genentech crystal structure of GNE-6776 (stick structure, top center) bound to USP7 (active site of which is ball-and-stick structure, bottom right).

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 the enzyme’s active-site cysteine. Scientists haven’t obtained, or at least haven’t published, small-molecule/USP7 crystal structures to guide drug discovery. And selective USP7 binding, with its potential for reduced side effects, has been elusive because many DUBs have similar structures and active sites.

[+]Enlarge
Credit: Nature
Forma-CRUK DUB Alliance crystal structure of FT671 (space-filling structure) bound to USP7 (active site of which is ball-and-stick structure, to the right).
Credit: Nature
Forma-CRUK DUB Alliance crystal structure of FT671 (space-filling structure) bound to USP7 (active site of which is ball-and-stick structure, to the right).

In the new studies, two research groups found the most selective USP7 inhibitors yet reported, and enzyme crystal structures they obtained reveal that the compounds bind at novel sites. Till Maurer and Ingrid E. Wertz of Genentech and coworkers used nuclear magnetic resonance spectroscopy-based screening and structure-based design to identify and optimize GNE-6640 and GNE-6776, which inhibit USP7 selectively compared with 36 other DUBs (Nature 2017, DOI: 10.1038/nature24006). The compounds block USP7 far from the active-site cysteine the enzyme has in common with other DUBs and kill tumors in cell culture and in live mice.

Stephanos Ioannidis of Forma Therapeutics, Andrew P. Turnbull of Cancer Research UK Therapeutic Discovery Laboratories, David Komander of the MRC Laboratory of Molecular Biology, Benedikt M. Kessler of the University of Oxford, Sylvie Urbé and Michael J. Clague of the University of Liverpool, and coworkers screened a Forma compound library to identify and refine the noncovalent inhibitor FT671 and the covalent inhibitor FT827 (Nature 2017, DOI: 10.1038/nature24451). The compounds block USP7 but not 38 other DUBs. They target USP7 at or near its active site but also interact with a uniquely structured pocket, and they inhibit the proliferation of cultured cancer cells and the growth of tumors in mice.

The groups used structural biology “to fine-tune inhibition of USP7 in a way that exploited differences between USP7 and other DUBs, maximizing the chances of obtaining high selectivity,” comments Michael Mattern, vice president of corporate affairs at Progenra, which is developing USP7 inhibitors. “How these findings translate to clinical utility, however, remains to be determined.”

Advertisement
X

Article:

This article has been sent to the following recipient:

Leave A Comment

*Required to comment