Small-molecule profiling for steroid receptor activity using a universal steroid receptor reporter assay
Copyright © 2021 Elsevier Ltd. All rights reserved..
A critical step in the development of novel drug candidates for the treatment of steroid related diseases is ensuring the absence of crosstalk with steroid receptors (SRs). Establishing this SR cross-reactivity profile requires multiple reporter assays as each SR associates with its unique enhancer region, a labor intensive and time-consuming approach. To overcome this need for multi-reporter assays, we established a steroid receptor inducible luciferase reporter assay (SRi-Luc) that allows side-by-side examination of agonistic and antagonistic properties of small-molecules on all steroid receptors. This state-of-the-art SRi-Luc consists of a unique alteration of four distinct keto-steroid- and estrogen response elements. As proof of principle, the SRi-Luc assay was used to profile a set of novel designed steroidal 1,2,3-triazoles. These triazolized steroidal compounds were developed via our in-house triazolization methodology, in which an enolizable ketone is converted into a triazolo-fused or -linked analog by treatment with a primary amine or ammonium salt in the presence of 4-nitrophenyl azide. From these designed steroidal 1,2,3-triazoles, six successfully reduced androgen receptor activity by 40 %. Although opted as antiandrogens, their cross-reactivity with other SRs was apparent in our SRi-Luc assay and rendered them unsuited for further antagonist development and clinical use. Overall, the SRi-Luc overcomes the need of multi-reporter assays for the profiling of small-molecules on all SRs. This not only reduces the risk of introducing biases, it as well accelerates early-stage drug discovery when designing particular SR selective (ant)agonists or characterizing off-target effects of lead molecules acting on any drug target.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:217 |
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| Enthalten in: |
The Journal of steroid biochemistry and molecular biology - 217(2022) vom: 01. März, Seite 106043 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Eerlings, Roy [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.04.2022 Date Revised 18.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jsbmb.2021.106043 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM334390168 |
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| 520 | |a Copyright © 2021 Elsevier Ltd. All rights reserved. | ||
| 520 | |a A critical step in the development of novel drug candidates for the treatment of steroid related diseases is ensuring the absence of crosstalk with steroid receptors (SRs). Establishing this SR cross-reactivity profile requires multiple reporter assays as each SR associates with its unique enhancer region, a labor intensive and time-consuming approach. To overcome this need for multi-reporter assays, we established a steroid receptor inducible luciferase reporter assay (SRi-Luc) that allows side-by-side examination of agonistic and antagonistic properties of small-molecules on all steroid receptors. This state-of-the-art SRi-Luc consists of a unique alteration of four distinct keto-steroid- and estrogen response elements. As proof of principle, the SRi-Luc assay was used to profile a set of novel designed steroidal 1,2,3-triazoles. These triazolized steroidal compounds were developed via our in-house triazolization methodology, in which an enolizable ketone is converted into a triazolo-fused or -linked analog by treatment with a primary amine or ammonium salt in the presence of 4-nitrophenyl azide. From these designed steroidal 1,2,3-triazoles, six successfully reduced androgen receptor activity by 40 %. Although opted as antiandrogens, their cross-reactivity with other SRs was apparent in our SRi-Luc assay and rendered them unsuited for further antagonist development and clinical use. Overall, the SRi-Luc overcomes the need of multi-reporter assays for the profiling of small-molecules on all SRs. This not only reduces the risk of introducing biases, it as well accelerates early-stage drug discovery when designing particular SR selective (ant)agonists or characterizing off-target effects of lead molecules acting on any drug target | ||
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| 700 | 1 | |a Barbakadze, Nana |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Tien |e verfasserin |4 aut | |
| 700 | 1 | |a Nadaraia, Nanuli |e verfasserin |4 aut | |
| 700 | 1 | |a Smeets, Elien |e verfasserin |4 aut | |
| 700 | 1 | |a Moris, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Handle, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a El Kharraz, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Devlies, Wout |e verfasserin |4 aut | |
| 700 | 1 | |a Voet, Arnout |e verfasserin |4 aut | |
| 700 | 1 | |a Dehaen, Wim |e verfasserin |4 aut | |
| 700 | 1 | |a Claessens, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Helsen, Christine |e verfasserin |4 aut | |
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