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

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.