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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Synthesis and evaluation of tiaprofenic acid-derived UCHL5 deubiquitinase inhibitors
Bioorganic & medicinal chemistry, v 30, 115931
15 Jan 2021
PMID: 33341501
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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The ubiquitin–proteasome system (UPS) plays an important role in maintaining protein homeostasis by degrading intracellular proteins. In the proteasome, poly-ubiquitinated proteins are deubiquitinated by three deubiquitinases (DUBs) associated with 19S regulatory particle before degradation via 20S core particle. Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) is one of three proteasome-associated DUBs that control the fate of ubiquitinated substrates implicated in cancer survival and progression. In this study, we have performed virtual screening of an FDA approved drug library with UCHL5 and discovered tiaprofenic acid (TA) as a potential binder. With molecular docking analysis and in-vitro DUB assay, we have designed, synthesized, and evaluated a series of TA derivatives for inhibition of UCHL5 activity. We demonstrate that one TA derivative, TAB2, acts as an inhibitor of UCHL5.
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Details
- Title
- Synthesis and evaluation of tiaprofenic acid-derived UCHL5 deubiquitinase inhibitors
- Creators
- Harshani S. Gurusingha Arachchige - Wayne State UniversityPoornima D.H. Herath Mudiyanselage - Wayne State UniversityGarrett C. VanHecke - Wayne State UniversityKush Patel - The Barbara Ann Karmanos Cancer InstituteHassan A. Cheaito - The Barbara Ann Karmanos Cancer InstituteQ. Ping Dou - The Barbara Ann Karmanos Cancer InstituteYoung-Hoon Ahn - Wayne State University
- Publication Details
- Bioorganic & medicinal chemistry, v 30, 115931
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Web of Science ID
- WOS:000612171300001
- Scopus ID
- 2-s2.0-85098741956
- Other Identifier
- 991020100078304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Chemistry, Organic