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dc.contributor.authorPippione, A.C.*
dc.contributor.authorCarnovale, I.M.*
dc.contributor.authorBonanni, D.*
dc.contributor.authorSini, Marcella*
dc.contributor.authorGoyal, P.*
dc.contributor.authorMarini, E.*
dc.contributor.authorPors, Klaus*
dc.contributor.authorAdinolfi, S.*
dc.contributor.authorZonari, D.*
dc.contributor.authorFestuccia, C.*
dc.contributor.authorWahlgren, W.Y.*
dc.contributor.authorFriemann, R.*
dc.contributor.authorBagnati, R.*
dc.contributor.authorBoschi, D.*
dc.contributor.authorOliaro-Bosso, S.*
dc.contributor.authorLolli, M.L.*
dc.date.accessioned2018-06-04T13:25:47Z
dc.date.available2018-06-04T13:25:47Z
dc.date.issued2018-04-25
dc.identifier.citationPippione AC, Carnovale IM, Bonanni D et al (2018) Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid. European Journal of Medicinal Chemistry. 150: 930-945.en_US
dc.identifier.urihttp://hdl.handle.net/10454/16082
dc.descriptionYesen_US
dc.description.abstractThe aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.en_US
dc.description.sponsorshipUniversity of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1016/j.ejmech.2018.03.040en_US
dc.rights© 2018 Elsevier. Reproduced in accordance with the publisher's self-archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.en_US
dc.subjectAldo-keto reductase 1C3en_US
dc.subjectAKR1C3en_US
dc.subject17β-HSD5en_US
dc.subjectProstate cancer (PCa)en_US
dc.subjectCRPCen_US
dc.subjectBioisosterismen_US
dc.subjectScaffold hoppingen_US
dc.subjectInhibitorsen_US
dc.subjectX-ray crystallographyen_US
dc.titlePotent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic aciden_US
dc.status.refereedYesen_US
dc.date.Accepted2018-03-14
dc.date.application2018-03-16
dc.typeArticleen_US
dc.type.versionAccepted Manuscripten_US


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