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

Abstract

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 <i>Plasmodium falciparum</i> M1 aminopeptidase (<i>Pf</i>A-M1). Herein, we describe the rationale that underpins the repurposing of <i>Pf</i>A-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. <i>N</i>-(2-(Hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (<b>6ad</b>) 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 <b>6ad</b> may be a useful lead for the development of anticancer agents.