Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue

J Med Chem. 2018 Dec 27;61(24):11250-11260. doi: 10.1021/acs.jmedchem.8b01381. Epub 2018 Dec 13.


Paired basic amino acid cleaving enzyme 4 (PACE4), a serine endoprotease of the proprotein convertases family, has been recognized as a promising target for prostate cancer. We previously reported a selective and potent peptide-based inhibitor for PACE4, named the multi-Leu peptide (Ac-LLLLRVKR-NH2 sequence), which was then modified into a more potent and stable compound named C23 with the following structure: Ac-dLeu-LLLRVK-Amba (Amba: 4-amidinobenzylamide). Despite improvements in both in vitro and in vivo profiles of C23, its selectivity for PACE4 over furin was significantly reduced. We examined other Arg-mimetics instead of Amba to regain the lost selectivity. Our results indicated that the replacement of Amba with 5-(aminomethyl)picolinimidamide increased affinity for PACE4 and restored selectivity. Our results also provide a better insight on how structural differences between S1 pockets of PACE4 and furin could be employed in the rational design of selective inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Humans
  • Male
  • Molecular Docking Simulation
  • Proprotein Convertases / antagonists & inhibitors*
  • Proprotein Convertases / chemistry
  • Proprotein Convertases / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology
  • Serine Endopeptidases / chemistry
  • Serine Endopeptidases / metabolism
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Serine Proteinase Inhibitors
  • PCSK6 protein, human
  • Proprotein Convertases
  • Serine Endopeptidases

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