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J Med Chem. 2018 Sep 27;61(18):8457-8467. doi: 10.1021/acs.jmedchem.8b01144. Epub 2018 Sep 17.

Increasing C-Terminal Hydrophobicity Improves the Cell Permeability and Antiproliferative Activity of PACE4 Inhibitors against Prostate Cancer Cell Lines.

Author information

1
Département de Chimie, Faculté des Sciences, Institut de Pharmacologie de Sherbrooke , Université de Sherbrooke , 3001, 12e Avenue Nord , Sherbrooke , Québec J1H 5N4 , Canada.
2
Département de Chirurgie/Urologie, Institut de Pharmacologie de Sherbrooke , Université de Sherbrooke , 3001, 12e Avenue Nord , Sherbrooke , Québec J1H 5N4 , Canada.

Abstract

The serine protease, PACE4, is a proprotein convertase that plays a substantial role in malignancy of prostate cancer. Our initial selective PACE4 inhibitor (Ac-LLLLRVKR-NH2) has evolved to the current lead compound C23 (Ac-dLeu-LLLRVK-Amba), which is active both in vitro and in vivo. By screening natural residues, except Cys, in C-terminal P1' position, it was established that increasing hydrophobicity was improving cell permeability, which was directly translated into PCa cells antiproliferative activity. This cell antiproliferation enhancement seems independent from effect of P1' residue on PACE4 affinity. Replacement of P1-Amba of C23 by Acpa (( S)-2-amino-3-(4-carbamimidoylphenyl)propanoic acid) followed by addition of tryptamine in P1' resulted in compound 32 exhibiting superior PCa cells antiproliferative activity over the reference compound C23 (3-fold). This study sheds light on key factors that improve cell penetrating property and antiproliferative activity of PACE4 inhibitors.

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