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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Apr 19

PMID 30996776

Citations 11

Authors

Marco L Lolli

Irene M Carnovale

Agnese C Pippione

Weixiao Y Wahlgren

Davide Bonanni

Elisabetta Marini

Daniele Zonari

Margherita Gallicchio

Valentina Boscaro

Parveen Goyal

Rosmarie Friemann

Barbara Rolando

Renzo Bagnati

Salvatore Adinolfi

Simonetta Oliaro-Bosso

Donatella Boschi

Affiliations

Soon will be listed here.

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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