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

ACS Med Chem Lett. 2019 Jan 28;10(4):437-443. doi: 10.1021/acsmedchemlett.8b00484.

Marco L Lolli ¹, Irene M Carnovale ¹, Agnese C Pippione ¹, Weixiao Y Wahlgren ², Davide Bonanni ¹, Elisabetta Marini ¹, Daniele Zonari ¹, Margherita Gallicchio ¹, Valentina Boscaro ¹, Parveen Goyal ², Rosmarie Friemann ², Barbara Rolando ¹, Renzo Bagnati ³, Salvatore Adinolfi ¹, Simonetta Oliaro-Bosso ¹, Donatella Boschi ¹

Affiliations

1 Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125 Turin, Italy.
2 Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg, Sweden.
3 Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Via La Masa 19, 20156 Milan, Italy.

PMID: 30996776 DOI: 10.1021/acsmedchemlett.8b00484

Abstract

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.

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