Protein degradation is crucial for maintaining the protein homeostasis in eukaryotic cells. Target proteins to be degraded are modified by poly-ubiquitination, which leads to degradation by 26S proteasome. In the proteasome, poly-ubiquitinated protein undergoes deubiquitylations before degradation at the 20S catalytic core subunits, which are mediated by deubiquitinases (DUB) associated with the proteasome. Ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5) is one of the three DUBs in the proteasome, which is located in the lid of the 19S regulatory subunits. Our preliminary data and literature showed a high level of expressions of UCHL5 in triple-negative breast cancer (TNBC) cell lines over non-TNBC, suggesting UCHL5 as a potential therapeutic target protein. However, there is no reported selective UCHL5 inhibitor. We have conducted a virtual screening of a FDA-approved drug library with UCHL5, identifying several lead compounds. Among hits, we have identified tiaprofenic acid (TA) as a potential inhibitor of UCHL5. Throughout computational docking analysis, we have designed and synthesized TA derivatives. Their inhibitory activities were evaluated by in-vitro UCHL5 enzyme assays, finding a potential inhibitor of UCHL5.

Developing inhibitors of UCHL5 deubiquitinase in the proteasome

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.