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Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators

Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inh...

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Detalles Bibliográficos
Autores principales: Antonyová, Veronika, Tatar, Ameneh, Brogyányi, Tereza, Kejík, Zdeněk, Kaplánek, Robert, Vellieux, Fréderic, Abramenko, Nikita, Sinica, Alla, Hajduch, Jan, Novotný, Petr, Masters, Bettie Sue, Martásek, Pavel, Jakubek, Milan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9505425/
https://www.ncbi.nlm.nih.gov/pubmed/36142763
http://dx.doi.org/10.3390/ijms231810850
Descripción
Sumario:Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC(50) = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.