Abstract
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.
Original language | English |
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Pages (from-to) | 8859-8874 |
Number of pages | 16 |
Journal | Journal of Medicinal Chemistry |
Volume | 61 |
Issue number | 19 |
Early online date | 13 Sept 2018 |
DOIs | |
Publication status | Published - 11 Oct 2018 |
Keywords
- Cell Proliferation/drug effects
- Depsipeptides/chemistry
- Enzyme Inhibitors/chemistry
- High-Throughput Screening Assays
- Humans
- Kallikreins/antagonists & inhibitors
- Models, Molecular
- Neoplasms/drug therapy
- Protein Conformation
- Structure-Activity Relationship
- Tumor Cells, Cultured