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

  • J Med Chem. 2018 Oct 11;61(19):8859-8874. doi: 10.1021/acs.jmedchem.8b01106.
Elena De Vita  1  2 ,  Peter Schüler  1 ,  Scott Lovell  3 ,  Jasmin Lohbeck  1 ,  Sven Kullmann  1 ,  Eitan Rabinovich  4 ,  Amiram Sananes  4 ,  Bernd Heßling  5 ,  Veronique Hamon  6 ,  Niv Papo  4 ,  Jochen Hess  7  8 ,  Edward W Tate  3 ,  Nikolas Gunkel  1  9 ,  Aubry K Miller  1  9
Affiliations
  • 1. Cancer Drug Development Group , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
  • 2. Biosciences Faculty , University of Heidelberg , Heidelberg 69120 , Germany.
  • 3. Department of Chemistry , Imperial College London , Exhibition Road , London SW7 2AZ , U.K.
  • 4. Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev , Ben-Gurion University of the Negev , Beer-Sheva 84105 , Israel.
  • 5. Center for Molecular Biology , University of Heidelberg , Heidelberg 69120 , Germany.
  • 6. European Screening Centre, Biocity Scotland , University of Dundee , Newhouse ML1 5UH , U.K.
  • 7. Department of Otorhinolaryngology, Head and Neck Surgery , Heidelberg University Hospital , Heidelberg 69120 , Germany.
  • 8. Research Group Molecular Mechanisms of Head and Neck Tumors , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
  • 9. German Cancer Consortium (DKTK) , Heidelberg 69120 , Germany.
PMID: 30212625 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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