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Volume 22
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10.3390/ijms22094537
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Article

Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons

by
Simona Selberg
1,
Li-Ying Yu
2,
Olesja Bondarenko
2,
Esko Kankuri
3,
Neinar Seli
4,
Vera Kovaleva
2,
Koit Herodes
1,
Mart Saarma
2 and
Mati Karelson
1,*
1
Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia
2
Institute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland
3
Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
4
Chemestmed, Ltd., 50411 Tartu, Estonia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(9), 4537; https://doi.org/10.3390/ijms22094537
Submission received: 17 March 2021 / Revised: 20 April 2021 / Accepted: 22 April 2021 / Published: 26 April 2021
(This article belongs to the Section Molecular Neurobiology)
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Abstract

The fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, is an important regulator of central nervous system development, neuronal signaling and disease. We present here the target-tailored development and biological characterization of small-molecule inhibitors of FTO. The active compounds were identified using high-throughput molecular docking and molecular dynamics screening of the ZINC compound library. In FTO binding and activity-inhibition assays the two best inhibitors demonstrated Kd = 185 nM; IC50 = 1.46 µM (compound 2) and Kd = 337 nM; IC50 = 28.9 µM (compound 3). Importantly, the treatment of mouse midbrain dopaminergic neurons with the compounds promoted cellular survival and rescued them from growth factor deprivation induced apoptosis already at nanomolar concentrations. Moreover, both the best inhibitors demonstrated good blood-brain-barrier penetration in the model system, 31.7% and 30.8%, respectively. The FTO inhibitors demonstrated increased potency as compared to our recently developed ALKBH5 m6A demethylase inhibitors in protecting dopamine neurons. Inhibition of m6A RNA demethylation by small-molecule drugs, as presented here, has therapeutic potential and provides tools for the identification of disease-modifying m6A RNAs in neurogenesis and neuroregeneration. Further refinement of the lead compounds identified in this study can also lead to unprecedented breakthroughs in the treatment of neurodegenerative diseases.
Keywords: FTO; ALKBH5; m6A; RNA; drug design; dopamine neurons FTO; ALKBH5; m6A; RNA; drug design; dopamine neurons

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MDPI and ACS Style

Selberg, S.; Yu, L.-Y.; Bondarenko, O.; Kankuri, E.; Seli, N.; Kovaleva, V.; Herodes, K.; Saarma, M.; Karelson, M. Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons. Int. J. Mol. Sci. 2021, 22, 4537. https://doi.org/10.3390/ijms22094537

AMA Style

Selberg S, Yu L-Y, Bondarenko O, Kankuri E, Seli N, Kovaleva V, Herodes K, Saarma M, Karelson M. Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons. International Journal of Molecular Sciences. 2021; 22(9):4537. https://doi.org/10.3390/ijms22094537

Chicago/Turabian Style

Selberg, Simona, Li-Ying Yu, Olesja Bondarenko, Esko Kankuri, Neinar Seli, Vera Kovaleva, Koit Herodes, Mart Saarma, and Mati Karelson. 2021. "Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons" International Journal of Molecular Sciences 22, no. 9: 4537. https://doi.org/10.3390/ijms22094537

APA Style

Selberg, S., Yu, L.-Y., Bondarenko, O., Kankuri, E., Seli, N., Kovaleva, V., Herodes, K., Saarma, M., & Karelson, M. (2021). Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons. International Journal of Molecular Sciences, 22(9), 4537. https://doi.org/10.3390/ijms22094537

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