Journal Article

DKFZ-2018-01772

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity.

De Vita, E. (First author)DKFZ* ; Schüler, P.DKFZ* ; Lovell, S. ; Lohbeck, J.DKFZ* ; Kullmann, S.DKFZ* ; Rabinovich, E. ; Sananes, A. ; Heßling, B.DKFZ* ; Hamon, V. ; Papo, N. ; Hess, J.DKFZ* ; Tate, E. W. ; Gunkel, N.DKFZ* ; Miller, A. (Last author)DKFZ*

2018
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.8b01106

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.

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Contributing Institute(s):

1. Wirkstoffforschung (G404)
2. Molekulare Grundlagen von HNO-Tumoren (G405)
3. DKTK Heidelberg (L101)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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