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

ABSTRACT: 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 (IC50 = 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.

SUBMITTER: Antonyova V 

PROVIDER: S-EPMC9505425 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-<i>b</i>]pyrrole Chelators.

Antonyová Veronika V   Tatar Ameneh A   Brogyányi Tereza T   Kejík Zdeněk Z   Kaplánek Robert R   Vellieux Fréderic F   Abramenko Nikita N   Sinica Alla A   Hajduch Jan J   Novotný Petr P   Masters Bettie Sue BS   Martásek Pavel P   Jakubek Milan M  

International journal of molecular sciences 20220916 18

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  ...[more]

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