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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Published in:International journal of molecular sciences 2022-09, Vol.23 (18), p.10850
Main Authors: 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
Format: Article
Language:English
Subjects:
Acids
Antitumor activity
Cancer
Cell growth
Chelating agents
Correlation coefficients
Dioxygenase
DNA methylation
Enzymes
Epigenetics
Gene expression
hydrazone
Hydrazones
Iron
Leukemia
Ligands
Localization
Medical prognosis
Mitochondria
Mitochondrial DNA
Molecular docking
Protein transport
Proteins
Pyrroles
pyrrolo[3,2-b]pyrrole
TET1 protein inhibitor
Thermophoresis
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms231810850