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Citation

BibTex format

@article{Panyain:2021:10.1039/d1md00218j,
author = {Panyain, N and Godinat, A and Thawani, AR and Lachiondo-Ortega, S and Mason, K and Elkhalifa, S and Smith, LM and Harrigan, JA and Tate, EW},
doi = {10.1039/d1md00218j},
journal = {RSC Medicinal Chemistry},
pages = {1935--1943},
title = {Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe},
url = {http://dx.doi.org/10.1039/d1md00218j},
volume = {12},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1 remain poorly understood. Herein, we report the characterization of UCHL1 covalent inhibitor MT16-001 based on a thiazole cyanopyrrolidine scaffold. In combination with chemical proteomics, a closely related activity-based probe (MT16-205) was used to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. Both compounds are selective for UCHL1 over other DUBs in intact cells but also engage a range of other targets with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson’s disease related protein PARK7, and glutamine amidotransferase. Taken together, these results underline the importance of robust profiling of activity-based probes as chemical tools and highlight the cyanopyrrolidine warhead as a versatile platform for liganding diverse classes of protein with reactive cysteine residues which can be used for further inhibitor screening, and as a starting point for inhibitor development.
AU  - Panyain,N
AU  - Godinat,A
AU  - Thawani,AR
AU  - Lachiondo-Ortega,S
AU  - Mason,K
AU  - Elkhalifa,S
AU  - Smith,LM
AU  - Harrigan,JA
AU  - Tate,EW
DO  - 10.1039/d1md00218j
EP  - 1943
PY  - 2021///
SN  - 2632-8682
SP  - 1935
TI  - Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe
T2  - RSC Medicinal Chemistry
UR  - http://dx.doi.org/10.1039/d1md00218j
UR  - https://pubs.rsc.org/en/Content/ArticleLanding/2021/MD/D1MD00218J
UR  - http://hdl.handle.net/10044/1/91507
VL  - 12
ER  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821