Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons
The fat mass and obesity-associated protein (FTO), an RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) demethylase, is an important regulator of central nervous system development, neuronal signaling and disease. We present here the target-tailored development and biologica...
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| Format: | Article |
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/9/4537 |
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| author | Simona Selberg Li-Ying Yu Olesja Bondarenko Esko Kankuri Neinar Seli Vera Kovaleva Koit Herodes Mart Saarma Mati Karelson |
| author_facet | Simona Selberg Li-Ying Yu Olesja Bondarenko Esko Kankuri Neinar Seli Vera Kovaleva Koit Herodes Mart Saarma Mati Karelson |
| author_sort | Simona Selberg |
| collection | DOAJ |
| description | The fat mass and obesity-associated protein (FTO), an RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 K<sub>d</sub> = 185 nM; IC<sub>50</sub> = 1.46 µM (compound <b>2</b>) and K<sub>d</sub> = 337 nM; IC<sub>50</sub> = 28.9 µM (compound <b>3</b>). 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 m<sup>6</sup>A demethylase inhibitors in protecting dopamine neurons. Inhibition of m<sup>6</sup>A RNA demethylation by small-molecule drugs, as presented here, has therapeutic potential and provides tools for the identification of disease-modifying m<sup>6</sup>A 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. |
| first_indexed | 2024-03-10T11:56:40Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:56:40Z |
| publishDate | 2021-04-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-169fda794e06476c8e01b30ac421cba42023-11-21T17:16:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01229453710.3390/ijms22094537Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine NeuronsSimona Selberg0Li-Ying Yu1Olesja Bondarenko2Esko Kankuri3Neinar Seli4Vera Kovaleva5Koit Herodes6Mart Saarma7Mati Karelson8Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, EstoniaInstitute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, FinlandDepartment of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandChemestmed, Ltd., 50411 Tartu, EstoniaInstitute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, FinlandInstitute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, EstoniaInstitute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, FinlandInstitute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, EstoniaThe fat mass and obesity-associated protein (FTO), an RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 K<sub>d</sub> = 185 nM; IC<sub>50</sub> = 1.46 µM (compound <b>2</b>) and K<sub>d</sub> = 337 nM; IC<sub>50</sub> = 28.9 µM (compound <b>3</b>). 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 m<sup>6</sup>A demethylase inhibitors in protecting dopamine neurons. Inhibition of m<sup>6</sup>A RNA demethylation by small-molecule drugs, as presented here, has therapeutic potential and provides tools for the identification of disease-modifying m<sup>6</sup>A 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.https://www.mdpi.com/1422-0067/22/9/4537FTOALKBH5m6ARNAdrug designdopamine neurons |
| spellingShingle | Simona Selberg Li-Ying Yu Olesja Bondarenko Esko Kankuri Neinar Seli Vera Kovaleva Koit Herodes Mart Saarma Mati Karelson Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons International Journal of Molecular Sciences FTO ALKBH5 m6A RNA drug design dopamine neurons |
| title | Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons |
| title_full | Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons |
| title_fullStr | Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons |
| title_full_unstemmed | Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons |
| title_short | Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons |
| title_sort | small molecule inhibitors of the rna m6a demethylases fto potently support the survival of dopamine neurons |
| topic | FTO ALKBH5 m6A RNA drug design dopamine neurons |
| url | https://www.mdpi.com/1422-0067/22/9/4537 |
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