Journal of Medicinal Chemistry p. 8859 - 8874 (2018)
Update date:2022-08-15
Topics:
De Vita, Elena
Schüler, Peter
Lovell, Scott
Lohbeck, Jasmin
Kullmann, Sven
Rabinovich, Eitan
Sananes, Amiram
He?ling, Bernd
Hamon, Veronique
Papo, Niv
Hess, Jochen
Tate, Edward W.
Gunkel, Nikolas
Miller, Aubry K.
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.
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