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@article{2262421,
author = {Antonyova, Veronika and Tatar, Ameneh and Brogyanyi, Tereza and Kejik, Zdenek and Kaplanek, Robert and Vellieux, Frederic and Abramenko, Nikita and Sinica, Alla and Hajduch, Jan and Novotny, Petr and Masters, Bettie Sue and Martasek, Pavel and Jakubek, Milan},
article_location = {Basel},
article_number = {18},
doi = {http://dx.doi.org/10.3390/ijms231810850},
keywords = {TET1 protein inhibitor; pyrrolo[3; 2-b]pyrrole; hydrazone; mitochondria},
language = {eng},
issn = {1422-0067},
journal = {International Journal of Molecular Sciences},
title = {Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators},
url = {https://www.mdpi.com/1422-0067/23/18/10850},
volume = {23},
year = {2022}
}
TY - JOUR
ID - 2262421
AU - Antonyova, Veronika - Tatar, Ameneh - Brogyanyi, Tereza - Kejik, Zdenek - Kaplanek, Robert - Vellieux, Frederic - Abramenko, Nikita - Sinica, Alla - Hajduch, Jan - Novotny, Petr - Masters, Bettie Sue - Martasek, Pavel - Jakubek, Milan
PY - 2022
TI - Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators
JF - International Journal of Molecular Sciences
VL - 23
IS - 18
SP - 10850
EP - 10850
PB - Multidisciplinary Digital Publishing Institute
SN - 14220067
KW - TET1 protein inhibitor
KW - pyrrolo[3
KW - 2-b]pyrrole
KW - hydrazone
KW - mitochondria
UR - https://www.mdpi.com/1422-0067/23/18/10850
N2 - 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 mu M), 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.
ER -
ANTONYOVA, Veronika, Ameneh TATAR, Tereza BROGYANYI, Zdenek KEJIK, Robert KAPLANEK, Frederic VELLIEUX, Nikita ABRAMENKO, Alla SINICA, Jan HAJDUCH, Petr NOVOTNY, Bettie Sue MASTERS, Pavel MARTASEK and Milan JAKUBEK. Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators. \textit{International Journal of Molecular Sciences}. Basel: Multidisciplinary Digital Publishing Institute, 2022, vol.~23, No~18, p.~10850-10874. ISSN~1422-0067. Available from: https://dx.doi.org/10.3390/ijms231810850.
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