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 language | English |
|---|---|
| Pages (from-to) | 7185-7209 |
| Number of pages | 25 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 62 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 8 Aug 2019 |
Cite this
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Novel Human Aminopeptidase N Inhibitors : Discovery and Optimization of Subsite Binding Interactions. / Lee, Jisook; Vinh, Natalie B.; Drinkwater, Nyssa; Yang, Wei; Kannan Sivaraman, Komagal; Schembri, Luke S.; Gazdik, Michelle; Grin, Peter M.; Butler, Georgina S.; Overall, Christopher M.; Charman, Susan A.; McGowan, Sheena; Scammells, Peter J.
In: Journal of Medicinal Chemistry, Vol. 62, No. 15, 08.08.2019, p. 7185-7209.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Novel Human Aminopeptidase N Inhibitors
T2 - Discovery and Optimization of Subsite Binding Interactions
AU - Lee, Jisook
AU - Vinh, Natalie B.
AU - Drinkwater, Nyssa
AU - Yang, Wei
AU - Kannan Sivaraman, Komagal
AU - Schembri, Luke S.
AU - Gazdik, Michelle
AU - Grin, Peter M.
AU - Butler, Georgina S.
AU - Overall, Christopher M.
AU - Charman, Susan A.
AU - McGowan, Sheena
AU - Scammells, Peter J.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071158549&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b00757
DO - 10.1021/acs.jmedchem.9b00757
M3 - Article
VL - 62
SP - 7185
EP - 7209
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -