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

V. Antonyová, A. Tatar, T. Brogyányi, Z. Kejík, R. Kaplánek, F. Vellieux, N. Abramenko, A. Sinica, J. Hajduch, P. Novotný, BS. Masters, P. Martásek, M. Jakubek

. 2022 ; 23 (18) : . [pub] 20220916

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc22024391

Grantová podpora
SVV260521, UNCE 204064, Progress Q26-38/LF1 and Q27/LF1 Charles University
LM2018133 (EATRIS-CZ) Ministry of Education Youth and Sports
No. TN01000013 and FW02020128. Technology Agency of the Czech Republic
CZ.02.1.01/0.0/0.0/16_019/0000785 Operational Programme Research, Development and Education
FV40120 Ministry of Industry and Trade
NU21-08-00407 Ministry of Health

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.

Citace poskytuje Crossref.org

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