Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity-based probe, could be used to pull down active endogenous KLK6.
Pharmacology, Toxicology and Pharmaceutical Science
5
9%
Biochemistry, Genetics and Molecular Biology
5
9%
Agricultural and Biological Sciences
3
5%
Medicine and Dentistry
2
4%
Other
3
5%
Unknown
19
35%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 27 February 2025.
All research outputs
#4,466,576
of 34,115,020 outputs
Outputs from Journal of Medicinal Chemistry
#7,132
of 28,245 outputs
Outputs of similar age
#65,583
of 378,307 outputs
Outputs of similar age from Journal of Medicinal Chemistry
#46
of 140 outputs
Altmetric has tracked 34,115,020 research outputs across all sources so far. Compared to these this one has done well and is in the 86th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 28,245 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.6. This one has gotten more attention than average, scoring higher than 74% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 378,307 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 82% of its contemporaries.
We're also able to compare this research output to 140 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 67% of its contemporaries.
