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| Home > Publications database > Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity. > print |
| 001 | 141252 | ||
| 005 | 20240229105123.0 | ||
| 024 | 7 | _ | |a 10.1021/acs.jmedchem.8b01106 |2 doi |
| 024 | 7 | _ | |a pmid:30212625 |2 pmid |
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| 024 | 7 | _ | |a 0095-9065 |2 ISSN |
| 024 | 7 | _ | |a 1520-4804 |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2018-01772 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a De Vita, Elena |0 P:(DE-He78)259bdc4ae1354441ccc5a5b8b01f7ccb |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity. |
| 260 | _ | _ | |a Washington, DC |c 2018 |b ACS |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1659614907_16658 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 317 - Translational cancer research (POF3-317) |0 G:(DE-HGF)POF3-317 |c POF3-317 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 700 | 1 | _ | |a Schüler, Peter |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Lovell, Scott |b 2 |
| 700 | 1 | _ | |a Lohbeck, Jasmin |0 P:(DE-He78)e61dcfcbebaf26a3144f45b3482f7385 |b 3 |u dkfz |
| 700 | 1 | _ | |a Kullmann, Sven |0 P:(DE-HGF)0 |b 4 |
| 700 | 1 | _ | |a Rabinovich, Eitan |b 5 |
| 700 | 1 | _ | |a Sananes, Amiram |b 6 |
| 700 | 1 | _ | |a Heßling, Bernd |0 P:(DE-HGF)0 |b 7 |
| 700 | 1 | _ | |a Hamon, Veronique |b 8 |
| 700 | 1 | _ | |a Papo, Niv |b 9 |
| 700 | 1 | _ | |a Hess, Jochen |0 P:(DE-He78)2e5f34f1c58eda4787a14c9dc139ca5f |b 10 |u dkfz |
| 700 | 1 | _ | |a Tate, Edward W |0 0000-0003-2213-5814 |b 11 |
| 700 | 1 | _ | |a Gunkel, Nikolas |0 P:(DE-HGF)0 |b 12 |
| 700 | 1 | _ | |a Miller, Aubry |0 P:(DE-He78)f0af962ddbc82430e947390b2f3f6e49 |b 13 |e Last author |u dkfz |
| 773 | _ | _ | |a 10.1021/acs.jmedchem.8b01106 |g Vol. 61, no. 19, p. 8859 - 8874 |0 PERI:(DE-600)1491411-6 |n 19 |p 8859 - 8874 |t Journal of medicinal chemistry |v 61 |y 2018 |x 1520-4804 |
| 909 | C | O | |p VDB |o oai:inrepo02.dkfz.de:141252 |
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| 913 | 1 | _ | |a DE-HGF |b Gesundheit |l Krebsforschung |1 G:(DE-HGF)POF3-310 |0 G:(DE-HGF)POF3-317 |3 G:(DE-HGF)POF3 |2 G:(DE-HGF)POF3-300 |4 G:(DE-HGF)POF |v Translational cancer research |x 0 |
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