A high-throughput effector screen identifies a novel small molecule scaffold for inhibition of ten-eleven translocation dioxygenase 2

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dc.contributor.authorPalei, Shubhendu
dc.contributor.authorWeisner, Jörn
dc.contributor.authorVogt, Melina
dc.contributor.authorGontla, Rajesh
dc.contributor.authorBuchmuller, Benjamin
dc.contributor.authorEhrt, Christiane
dc.contributor.authorGrabe, Tobias
dc.contributor.authorKleinbölting, Silke
dc.contributor.authorMüller, Matthias
dc.contributor.authorClever, Guido H.
dc.contributor.authorRauh, Daniel
dc.contributor.authorSummerer, Daniel
dc.date.accessioned2023-03-27T06:40:25Z
dc.date.available2023-03-27T06:40:25Z
dc.date.issued2022-09-02
dc.description.abstractTen-eleven translocation dioxygenases (TETs) are the erasers of 5-methylcytosine (mC), the central epigenetic regulator of mammalian DNA. TETs convert mC to three oxidized derivatives with unique physicochemical properties and inherent regulatory potential, and it initializes active demethylation by the base excision repair pathway. Potent small molecule inhibitors would be useful tools to study TET functions by conditional control. To facilitate the discovery of such tools, we here report a high-throughput screening pipeline and its application to screen and validate 31.5k compounds for inhibition of TET2. Using a homogenous fluorescence assay, we discover a novel quinoline-based scaffold that we further validate with an orthogonal semi-high throughput MALDI-MS assay for direct monitoring of substrate turnover. Structure–activity relationship (SAR) studies involving >20 derivatives of this scaffold led to the identification of optimized inhibitors, and together with computational studies suggested a plausible model for its mode of action.en
dc.identifier.urihttp://hdl.handle.net/2003/41311
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-23154
dc.language.isoende
dc.relation.ispartofseriesRSC medicinal chemistry;13(12)
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.subject.ddc570
dc.subject.ddc540
dc.subject.rswkEpigenetikde
dc.subject.rswkGenregulationde
dc.subject.rswkSäugetierede
dc.subject.rswkDNSde
dc.subject.rswkFluoreszenz-Resonanz-Energie-Transferde
dc.subject.rswkStruktur-Aktivitäts-Beziehungde
dc.titleA high-throughput effector screen identifies a novel small molecule scaffold for inhibition of ten-eleven translocation dioxygenase 2en
dc.typeTextde
dc.type.publicationtypearticlede
dcterms.accessRightsopen access
eldorado.secondarypublicationtruede
eldorado.secondarypublication.primarycitationRSC Med. Chem., 2022,13, 1540-1548de
eldorado.secondarypublication.primaryidentifierhttps://doi.org/10.1039/D2MD00186Ade

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