Imperial College London
Portrait Picture

Prof Ed Tate

Faculty of Natural Sciences, Department of Chemistry

GSK Chair in Chemical Biology
 
 
 
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Contact

 

+44 (0)20 7594 3752e.tate Website CV

 
 
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Assistant

 

Ms Agnes Lee +44 (0)20 7594 9852

 
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Location

 

301BMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Zhang:2022:10.1021/jacs.2c07378,
author = {Zhang, L and Lovell, S and De, Vita E and Jagtap, P and Lucy, D and Goya, Grocin A and Kjaer, S and Borg, A and Henning, J and Miller, A and Tate, E},
doi = {10.1021/jacs.2c07378},
journal = {Journal of the American Chemical Society},
pages = {22493--22504},
title = {A KLK6 activity-based probe reveals a role for KLK6 activity in pancreatic cancer cell invasion},
url = {http://dx.doi.org/10.1021/jacs.2c07378},
volume = {144},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M–1 s–1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases.
AU  - Zhang,L
AU  - Lovell,S
AU  - De,Vita E
AU  - Jagtap,P
AU  - Lucy,D
AU  - Goya,Grocin A
AU  - Kjaer,S
AU  - Borg,A
AU  - Henning,J
AU  - Miller,A
AU  - Tate,E
DO  - 10.1021/jacs.2c07378
EP  - 22504
PY  - 2022///
SN  - 0002-7863
SP  - 22493
TI  - A KLK6 activity-based probe reveals a role for KLK6 activity in pancreatic cancer cell invasion
T2  - Journal of the American Chemical Society
UR  - http://dx.doi.org/10.1021/jacs.2c07378
UR  - http://hdl.handle.net/10044/1/100993
VL  - 144
ER  -
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