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Ubiquitin C‐Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine‐Based Inhibitor
Author(s) -
Krabill Aaron D.,
Chen Hao,
Hussain Sajjad,
Feng Chao,
Abdullah Ammara,
Das Chittaranjan,
Aryal Uma K.,
Post Carol Beth,
Wendt Michael K.,
Galardy Paul J.,
Flaherty Daniel P.
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900434
Subject(s) - deubiquitinating enzyme , ubiquitin , oncogene , cancer , cancer research , biology , enzyme , in vivo , hydrolase , biochemistry , chemistry , microbiology and biotechnology , gene , genetics , cell cycle
The deubiquitinase (DUB) ubiquitin C‐terminal hydrolase L1 (UCHL1) is expressed primarily in the central nervous system under normal physiological conditions. However, UCHL1 is overexpressed in various aggressive forms of cancer with strong evidence supporting UCHL1 as an oncogene in lung, glioma, and blood cancers. In particular, the level of UCHL1 expression in these cancers correlates with increased invasiveness and metastatic behavior, as well as poor patient prognosis. Although UCHL1 is considered an oncogene with potential as a therapeutic target, there remains a significant lack of useful small‐molecule probes to pharmacologically validate in vivo targeting of the enzyme. Herein, we describe the characterization of a new covalent cyanopyrrolidine‐based UCHL1 inhibitory scaffold in biochemical and cellular studies to better understand the utility of this inhibitor in elucidating the role of UCHL1 in cancer biology.