Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

Aminopeptidase
N (APN/CD13) is a zinc-dependent M1 aminopeptidase
that contributes to cancer progression by promoting angiogenesis,
metastasis, and tumor invasion. We have previously identified hydroxamic
acid-containing analogues that are potent inhibitors of the APN homologue
from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe
the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic
acid analogues were developed using a structure-based design approach
and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)­ethyl)-4-(methylsulfonamido)­benzamide
(6ad) proved to be an extremely potent inhibitor of APN
activity in vitro, selective against other zinc-dependent enzymes
such as matrix metalloproteases, and possessed limited cytotoxicity
against Ad293 cells and favorable physicochemical and metabolic stability
properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.