Structure-activity relationship studies of dipeptide-based hepsin inhibitors with Arg bioisosteres

Bioorg Chem. 2021 Feb:107:104521. doi: 10.1016/j.bioorg.2020.104521. Epub 2020 Nov 28.

Abstract

Hepsin is a type II transmembrane serine protease (TTSP) associated with cell proliferation and overexpressed in several types of cancer including prostate cancer (PCa). Because of its significant role in cancer progression and metastasis, hepsin is an attractive protein as a potential therapeutic and diagnostic biomarker for PCa. Based on the reported Leu-Arg dipeptide-based hepsin inhibitors, we performed structural modification and determined in vitro hepsin- and matriptase-inhibitory activities. Comprehensive structure-activity relationship studies identified that the p-guanidinophenylalanine-based dipeptide analog 22a exhibited a strong hepsin-inhibitory activity (Ki = 50.5 nM) and 22-fold hepsin selectivity over matriptase. Compound 22a could be a prototype molecule for structural optimization of dipeptide-based hepsin inhibitors.

Keywords: Bioisostere; Dipeptide; Hepsin; Prostate cancer; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Dipeptides / chemistry*
  • Dipeptides / metabolism
  • Drug Design
  • Enzyme Assays
  • Humans
  • Molecular Docking Simulation
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / chemistry
  • Protein Binding
  • Serine Endopeptidases / chemistry
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / metabolism
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Serine Proteinase Inhibitors
  • 4-guanidinophenylalanine
  • Phenylalanine
  • Serine Endopeptidases
  • matriptase
  • HPN protein, human