Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

Elena De Vita, Peter Schüler, Scott Lovell, Jasmin Lohbeck, Sven Kullmann, Eitan Rabinovich, Amiram Sananes, Bernd Heßling, Veronique Hamon, Niv Papo, Jochen Hess, Edward W Tate, Nikolas Gunkel, Aubry K Miller

Research output: Contribution to journalArticlepeer-review

22 Citations (SciVal)


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 languageEnglish
Pages (from-to)8859-8874
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number19
Early online date13 Sept 2018
Publication statusPublished - 11 Oct 2018


  • 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


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