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Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3

Journal article
Authors M. L. Lolli
I. M. Carnovale
A. C. Pippione
Weixiao Yuan Wahlgren
D. Bonanni
E. Marini
D. Zonari
M. Gallicchio
V. Boscaro
Parveen Goyal
Rosmarie Friemann
B. Rolando
R. Bagnati
S. Adinolfi
S. Oliaro-Bosso
D. Boschi
Published in Acs Medicinal Chemistry Letters
Volume 10
Issue 4
Pages 437-443
ISSN 1948-5875
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Pages 437-443
Language en
Keywords AKR1C3, Bioisosterism, Indomethacin, Prostate cancer, Scaffold hopping, X-ray crystallography
Subject categories Medicinal Chemistry


Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer. © 2019 American Chemical Society.

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