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

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.