Four papers in the last two weeks describing inhibitors of the ubiquitin-regulating protein USP7 could signal an important breakthrough in the ability to drug DUBs, a class of enzymes that has been stubbornly intractable until now. The activity is the latest example of drug developers turning to the proteasome to control aberrant protein activity in cancer and other diseases.
USP7 is a deubiquitinase (DUB) that has drawn attention because it acts to regulate levels of p53, a key tumor suppressor protein that has eluded translation for decades.
The papers put USP7 in the running to emerge as the first target in the DUB family to enter the clinic.
DUBs prevent degradation of proteins by removing ubiquitins -- small proteins added by ligases that mark proteins for proteasomal degradation. By inhibiting DUBs, the goal is to increase degradation of the target proteins.
The enzymes act along the same idea, but converse strategy, to E3 ligases and targeted protein degradation, both of which eliminate proteins by adding ubiquitin to deliberately shuttle them off to the proteasome (see "Degrading Targets").
Figure: Degrading targets
Inhibiting deubiquitinating enzymes (DUBs) is just one way to drive degradation of target proteins. Biotechs and pharmas are also using two other techniques -- ubiquitin ligase modulation and targeted protein degradation -- to mark select proteins for degradation by the proteasome.
1. Ubiquitin ligase modulation. The ubiquitin ligase is a protein complex that adds ubiquitin (u) to target proteins. Once ubiquitinated, target proteins are sent to the proteasome for degradation. At least one company, Celgene Corp. (NASDAQ:CELG), markets and is developing modulators of the E3 ubiquitin ligase complex protein cereblon (CRBN) to enhance ubiquitination of select substrates, and Progenra Inc. is developing molecules that bind undisclosed domains of E3 ligases.
2. DUB inhibition. Rather than directly increasing ubiquitination, DUB inhibitors work by blocking activity of the DUBs that remove ubiquitin from target proteins. Preventing ubiquitin removal increases degradation of target proteins by the proteasome. At least 10 companies have DUB inhibitors