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 journalArticle

6 Citations (Scopus)

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 languageEnglish
Pages (from-to)8859-8874
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number19
Early online date13 Sep 2018
DOIs
Publication statusPublished - 11 Oct 2018

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    De Vita, E., Schüler, P., Lovell, S., Lohbeck, J., Kullmann, S., Rabinovich, E., Sananes, A., Heßling, B., Hamon, V., Papo, N., Hess, J., Tate, E. W., Gunkel, N., & Miller, A. K. (2018). Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity. Journal of Medicinal Chemistry, 61(19), 8859-8874. https://doi.org/10.1021/acs.jmedchem.8b01106