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

Hongmok Kwon, YunHye Kim, Kieung Park, Soo An Choi, Sang Hyun Son, Youngjoo Byun

Research output: Contribution to journalArticle

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 22 nM and 3 nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.

Original languageEnglish (US)
Pages (from-to)310-314
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number2
DOIs
StatePublished - Jan 15 2016
Externally publishedYes

Keywords

  • Dipeptides
  • Hepsin
  • Prostate cancer
  • Serine protease

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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