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BibTex format

author = {Lovell, S and Zhang, L and Kryza, T and Neodo, A and Bock, N and De, Vita E and Williams, E and Engelsberger, E and Xu, C and Bakker, A and Maneiro, M and Tanaka, R and Bevan, C and Clements, J and Tate, E},
doi = {10.1021/jacs.1c03950},
journal = {Journal of the American Chemical Society},
pages = {8911--8924},
title = {A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer},
url = {},
volume = {143},
year = {2021}

RIS format (EndNote, RefMan)

AB - Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP), we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs, we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.
AU - Lovell,S
AU - Zhang,L
AU - Kryza,T
AU - Neodo,A
AU - Bock,N
AU - De,Vita E
AU - Williams,E
AU - Engelsberger,E
AU - Xu,C
AU - Bakker,A
AU - Maneiro,M
AU - Tanaka,R
AU - Bevan,C
AU - Clements,J
AU - Tate,E
DO - 10.1021/jacs.1c03950
EP - 8924
PY - 2021///
SN - 0002-7863
SP - 8911
TI - A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer
T2 - Journal of the American Chemical Society
UR -
UR -
VL - 143
ER -