Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors

Bioorg Med Chem Lett. 2016 Jan 15;26(2):310-314. doi: 10.1016/j.bmcl.2015.12.023. Epub 2015 Dec 8.

Abstract

Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22nM and 3nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.

Keywords: Dipeptides; Hepsin; Prostate cancer; Serine protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / pharmacology*
  • Dipeptides / chemical synthesis
  • Dipeptides / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Recombinant Proteins / metabolism
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / pharmacology*
  • Thiazoles / chemical synthesis
  • Thiazoles / pharmacology*

Substances

  • Benzothiazoles
  • Dipeptides
  • Recombinant Proteins
  • Serine Proteinase Inhibitors
  • Thiazoles
  • acetyl-leucyl-arginyl-ketobenzothiazole
  • acetyl-leucyl-arginyl-ketothiazole
  • leucylarginine
  • Serine Endopeptidases
  • hepsin
  • matriptase