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000141252 0247_ $$2doi$$a10.1021/acs.jmedchem.8b01106
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000141252 0247_ $$2ISSN$$a0022-2623
000141252 0247_ $$2ISSN$$a0095-9065
000141252 0247_ $$2ISSN$$a1520-4804
000141252 0247_ $$2ISSN$$a1943-2992
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000141252 037__ $$aDKFZ-2018-01772
000141252 041__ $$aeng
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000141252 1001_ $$0P:(DE-He78)259bdc4ae1354441ccc5a5b8b01f7ccb$$aDe Vita, Elena$$b0$$eFirst author$$udkfz
000141252 245__ $$aDepsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity.
000141252 260__ $$aWashington, DC$$bACS$$c2018
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000141252 520__ $$aKallikrein-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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000141252 7001_ $$0P:(DE-HGF)0$$aSchüler, Peter$$b1
000141252 7001_ $$aLovell, Scott$$b2
000141252 7001_ $$0P:(DE-He78)e61dcfcbebaf26a3144f45b3482f7385$$aLohbeck, Jasmin$$b3$$udkfz
000141252 7001_ $$0P:(DE-HGF)0$$aKullmann, Sven$$b4
000141252 7001_ $$aRabinovich, Eitan$$b5
000141252 7001_ $$aSananes, Amiram$$b6
000141252 7001_ $$0P:(DE-HGF)0$$aHeßling, Bernd$$b7
000141252 7001_ $$aHamon, Veronique$$b8
000141252 7001_ $$aPapo, Niv$$b9
000141252 7001_ $$0P:(DE-He78)2e5f34f1c58eda4787a14c9dc139ca5f$$aHess, Jochen$$b10$$udkfz
000141252 7001_ $$00000-0003-2213-5814$$aTate, Edward W$$b11
000141252 7001_ $$0P:(DE-HGF)0$$aGunkel, Nikolas$$b12
000141252 7001_ $$0P:(DE-He78)f0af962ddbc82430e947390b2f3f6e49$$aMiller, Aubry$$b13$$eLast author$$udkfz
000141252 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.8b01106$$gVol. 61, no. 19, p. 8859 - 8874$$n19$$p8859 - 8874$$tJournal of medicinal chemistry$$v61$$x1520-4804$$y2018
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