Synthesis and Structure-Activity Relationships of N-(4-Benzamidino)-Oxazolidinones: Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6

Elena De Vita, Niels Smits, Helma van den Hurk, Elizabeth M. Beck, Joanne Hewitt, Gemma Baillie, Emily Russell, Andrew Pannifer, Véronique Hamon, Angus Morrison, Stuart P. McElroy, Philip Jones, Natalia A. Ignatenko, Nikolas Gunkel, Aubry K. Miller

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)-3-(4-carbamimidoylphenyl)-N-((S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) and 34 ((5R)-3-(6-carbamimidoylpyridin-3-yl)-N-((1S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) have single-digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.

Original languageEnglish (US)
Pages (from-to)79-95
Number of pages17
JournalChemMedChem
Volume15
Issue number1
DOIs
StatePublished - Jan 7 2020

Keywords

  • Drug Discovery
  • High-throughput screening
  • Medicinal Chemistry
  • Protease inhibitors
  • Structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    De Vita, E., Smits, N., van den Hurk, H., Beck, E. M., Hewitt, J., Baillie, G., Russell, E., Pannifer, A., Hamon, V., Morrison, A., McElroy, S. P., Jones, P., Ignatenko, N. A., Gunkel, N., & Miller, A. K. (2020). Synthesis and Structure-Activity Relationships of N-(4-Benzamidino)-Oxazolidinones: Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6. ChemMedChem, 15(1), 79-95. https://doi.org/10.1002/cmdc.201900536