期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 144, 期 49, 页码 22493-22504出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c07378
关键词
-
资金
- Cancer Research UK [C24523/A25192, C29637/A20183, C29637/A21451]
- EPSRC Centre for Doctoral Training in Physical Sciences Innovation in Chemical Biology for Bioindustry and Healthcare [EP/LO15498/1]
- European Union Horizon 2020 Program [890900]
- Worldwide Cancer Research [19-0059]
- EPSRC
- NIH [P41-GM103311]
- Marie Curie Actions (MSCA) [890900] Funding Source: Marie Curie Actions (MSCA)
Pancreatic cancer has the lowest survival rate among common cancers due to late diagnosis and limited treatment options. The kallikreinrelated peptidase (KLK) family of secreted serine proteases, specifically KLK6, has emerged as a potential target for pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) has hindered the validation of these enzymes as targets or biomarkers. In this study, potent and selective ABPs for KLK6 were developed, enabling the detection of KLK6 activity in PDAC cell lines and providing insights into KLK6-mediated invasion pathways.
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 kallikreinrelated 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据