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

Jisook Lee, Natalie B. Vinh, Nyssa Drinkwater, Wei Yang, Komagal Kannan Sivaraman, Luke S. Schembri, Michelle Gazdik, Peter M. Grin, Georgina S. Butler, Christopher M. Overall, Susan A. Charman, Sheena McGowan, Peter J. Scammells

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)7185-7209
Number of pages25
JournalJournal of Medicinal Chemistry
Volume62
Issue number15
DOIs
Publication statusPublished - 8 Aug 2019

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