%0 Journal Article
%A De Vita, Elena
%A Schüler, Peter
%A Lovell, Scott
%A Lohbeck, Jasmin
%A Kullmann, Sven
%A Rabinovich, Eitan
%A Sananes, Amiram
%A Heßling, Bernd
%A Hamon, Veronique
%A Papo, Niv
%A Hess, Jochen
%A Tate, Edward W
%A Gunkel, Nikolas
%A Miller, Aubry
%T Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity.
%J Journal of medicinal chemistry
%V 61
%N 19
%@ 1520-4804
%C Washington, DC
%I ACS
%M DKFZ-2018-01772
%P 8859 - 8874
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30212625
%R 10.1021/acs.jmedchem.8b01106
%U https://inrepo02.dkfz.de/record/141252