{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:53:24Z","timestamp":1792029204007,"version":"4.4.0"},"reference-count":55,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chemestmed, Ltd.","award":["11-18\/IK\/90"],"award-info":[{"award-number":["11-18\/IK\/90"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u00b5M (compound 2) and Kd = 337 nM; IC50 = 28.9 \u00b5M (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.<\/jats:p>","DOI":"10.3390\/ijms22094537","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T02:31:43Z","timestamp":1619490703000},"page":"4537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons"],"prefix":"10.3390","volume":"22","author":[{"given":"Simona","family":"Selberg","sequence":"first","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-1365","authenticated-orcid":false,"given":"Olesja","family":"Bondarenko","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-8773","authenticated-orcid":false,"given":"Esko","family":"Kankuri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neinar","family":"Seli","sequence":"additional","affiliation":[{"name":"Chemestmed, Ltd., 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Kovaleva","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koit","family":"Herodes","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart","family":"Saarma","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mati","family":"Karelson","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1021\/acschembio.6b00960","article-title":"Chemical Modifications to RNA: A New Layer of Gene Expression Regulation","volume":"12","author":"Song","year":"2017","journal-title":"ACS Chem. 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