Ubiquitin C-Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine-Based Inhibitor

Aaron D Krabill; Hao Chen; Sajjad Hussain; Chao Feng; Ammara Abdullah; Chittaranjan Das; Uma K Aryal; Carol Beth Post; Michael K Wendt; Paul J Galardy; Daniel P Flaherty

doi:10.1002/cbic.201900434

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Ubiquitin C-Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine-Based Inhibitor

Journal article

Peer reviewed

Ubiquitin C-Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine-Based Inhibitor

Aaron D Krabill, Hao Chen, Sajjad Hussain, Chao Feng, Ammara Abdullah, Chittaranjan Das, Uma K Aryal, Carol Beth Post, Michael K Wendt, Paul J Galardy, …

Chembiochem : a European journal of chemical biology, Vol.21(5), pp.712-722

03/02/2020

DOI: 10.1002/cbic.201900434

PMCID: PMC7042063

PMID: 31449350

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Abstract

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.

Binding Sites

Cell Line

Enzyme Inhibitors - chemical synthesis

Enzyme Inhibitors - chemistry

Enzyme Inhibitors - metabolism

Humans

Molecular Structure

Protein Binding

Protein Structure, Secondary

Ubiquitin Thiolesterase - antagonists & inhibitors

Ubiquitin Thiolesterase - metabolism

Details

Title: Subtitle: Ubiquitin C-Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine-Based Inhibitor
Creators: Aaron D Krabill - Purdue University West Lafayette
Hao Chen - Purdue University West Lafayette
Sajjad Hussain - Mayo Clinic
Chao Feng - Purdue University West Lafayette
Ammara Abdullah - Purdue University West Lafayette
Chittaranjan Das - Purdue University Northwest
Uma K Aryal - Purdue University West Lafayette
Carol Beth Post - Purdue University West Lafayette
Michael K Wendt - Purdue University West Lafayette
Paul J Galardy - Mayo Clinic
Daniel P Flaherty - Purdue University West Lafayette
Resource Type: Journal article
Publication Details: Chembiochem : a European journal of chemical biology, Vol.21(5), pp.712-722
DOI: 10.1002/cbic.201900434
PMID: 31449350
PMCID: PMC7042063
NLM abbreviation: Chembiochem
ISSN: 1439-4227
eISSN: 1439-7633
Grant note: R01 GM039478 / NIGMS NIH HHS P30 CA023168 / NCI NIH HHS
Language: English
Date published: 03/02/2020
Academic Unit: Internal Medicine
Record Identifier: 9984460330902771

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