Activity-based protein profiling reveals targets of a cyanopyrrolidine probe

Congratulations to former PhD student Dr Nattawadee Panyain for publishing in RSC Medicinal Chemistry

UCHL1 is a deubiquitinating (DUB) enzyme that is involved in various cancers, and liver and lung fibrosis. This enzyme is therefore of interest as a potential drug target, however the functions and substrates of UCHL1 are poorly understood.

In this collaborative paper, the authors characterize covalent inhibitors of UCHL1 and use chemical proteomics to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. The findings showed that molecules were selective for UCHL1, over other DUBs, but also engaged a range of other targets. These were displayed with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson's disease related protein PARK7, and glutamine amidotransferase.

We would like to thank Cancer Research UK, the Royal Thai Government, the UK Medical Research Council, and the Wellcome Trust for their generous funding.

Congratulations to all involved!