Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

TY - JOUR

T1 - Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

AU - De Vita, Elena

AU - Schüler, Peter

AU - Lovell, Scott

AU - Lohbeck, Jasmin

AU - Kullmann, Sven

AU - Rabinovich, Eitan

AU - Sananes, Amiram

AU - Heßling, Bernd

AU - Hamon, Veronique

AU - Papo, Niv

AU - Hess, Jochen

AU - Tate, Edward W.

AU - Gunkel, Nikolas

AU - Miller, Aubry K.

N1 - This work was supported in part by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science, Technology and Space (MOST) (Grants GR-2495 to N.P. and A.K.M) and by the German Cancer Aid (Grant 70112000 to J.H.). E.D.V. was supported by an EMBO short-term fellowship (Grant STF7471). S.L. was supported by the EPSRC Centre for Doctoral Training in Physical Sciences Innovation in Chemical Biology for Bioindustry and Healthcare (Grant EP/LO15498/ 1). Further financial support from the Helmholtz Drug Initiative and the German Cancer Consortium (DKTK) is gratefully acknowledged.

PY - 2018/10/11

Y1 - 2018/10/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85054210171

U2 - 10.1021/acs.jmedchem.8b01106

DO - 10.1021/acs.jmedchem.8b01106

M3 - Article

C2 - 30212625

AN - SCOPUS:85054210171

SN - 0022-2623

VL - 61

SP - 8859

EP - 8874

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -