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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. Copyright © 2021 Elsevier Ltd. All rights reserved.


Roy Eerlings, Nana Barbakadze, Tien Nguyen, Nanuli Nadaraia, Elien Smeets, Lisa Moris, Florian Handle, Sarah El Kharraz, Wout Devlies, Arnout Voet, Wim Dehaen, Frank Claessens, Christine Helsen. Small-molecule profiling for steroid receptor activity using a universal steroid receptor reporter assay. The Journal of steroid biochemistry and molecular biology. 2022 Mar;217:106043

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PMID: 34902544

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