Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor

Anna Kwiatkowska , Frédéric Couture , Christine Levesque , Kévin Ly , Roxane Desjardins , Sophie Beauchemin , Adam Prahl , Bernard Lammek , Witold Neugebauer , Yves L. Dory , Robert Day


PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure–activity relationship studies. A variety of ML-peptide analogues modified at the P8–P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide.
Author Anna Kwiatkowska
Anna Kwiatkowska,,
, Frédéric Couture
Frédéric Couture,,
, Christine Levesque
Christine Levesque,,
, Kévin Ly
Kévin Ly,,
, Roxane Desjardins
Roxane Desjardins,,
, Sophie Beauchemin
Sophie Beauchemin,,
, Adam Prahl (FCh / DOCh / LChB)
Adam Prahl,,
- Laboratory of Chemistry of Biopolymers
, Bernard Lammek (FCh / DOCh / LChB)
Bernard Lammek,,
- Laboratory of Chemistry of Biopolymers
, Witold Neugebauer
Witold Neugebauer,,
, Yves L. Dory
Yves L. Dory,,
et al.`
Journal seriesJournal of Medicinal Chemistry, ISSN 0022-2623 [1520-4804], (A 45 pkt)
Issue year2014
Publication size in sheets0.55
Languageen angielski
Score (nominal)45
ScoreMinisterial score = 45.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 45.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2014 = 5.447 (2) - 2014=5.464 (5)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.