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  3. Structure-based virtual screening, in vitro and in silico analysis identified novel potent m6A demethylase FTO inhibitors as promising neurotherapeutic agents

Structure-based virtual screening, in vitro and in silico analysis identified novel potent m6A demethylase FTO inhibitors as promising neurotherapeutic agents

  • Eur J Med Chem. 2026 Aug 5:312:118852. doi: 10.1016/j.ejmech.2026.118852.
Alba Irisarri 1,  Aina Bellver-Sanchis 1,  Bhanwar Singh Choudhary 2,  Ana Mallo-Abreu 3,  Luis Labrador 4,  Gemma Casadesus 4,  Belén Pérez 5,  Abhisek Jana 6,  Deb Ranjan Banerjee 6,  Isabel Iriepa 7,  M Isabel Loza 8,  José Brea 8,  Cristina Val 8,  Mercè Pallàs 9,  Diego Muñoz-Torrero 10,  Christian Griñán-Ferré 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona, Spain; Institute of Neurosciences of the University of Barcelona, University of Barcelona, Barcelona, Spain.
  • 2 Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, India.
  • 3 Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona, Spain; Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal 643, Barcelona, Spain.
  • 4 Department of Pharmacology and Therapeutics, Health Science Center-University of Florida, Gainesville, FL, USA.
  • 5 Department of Pharmacology, Therapeutic and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 6 Department of Chemistry, National Institute of Technology Durgapur, Durgapur, India.
  • 7 Universidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR), Alcalá de Henares, Madrid, 28805, Spain; Grupo DISCOBAC, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Alcalá de Henares, Madrid, 28805, Spain.
  • 8 Innopharma Drug Screening and Pharmacogenomics Platform, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela (SERGAS), Trav. Choupana s/n, Santiago de Compostela, 15706, Spain.
  • 9 Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona, Spain; Institute of Neurosciences of the University of Barcelona, University of Barcelona, Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
  • 10 Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona, Spain; Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal 643, Barcelona, Spain. Electronic address: [email protected].
  • 11 Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona, Spain; Institute of Neurosciences of the University of Barcelona, University of Barcelona, Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: [email protected].
PMID: 42024965 DOI: 10.1016/j.ejmech.2026.118852
Abstract

Dysregulation of the m6A RNA demethylase FTO has been implicated in neurodegeneration, but brain-penetrant, selective inhibitors remain scarce. Here, we used structure-based virtual screening of a CNS-oriented library to identify novel FTO inhibitors and characterized their permeability, selectivity, and pharmacological profiles. Among them, compound VI showed low-micromolar inhibition of human FTO, selectivity over ALKBH5, high PAMPA-BBB permeability, and oral exposure with measurable plasma levels, moderate brain penetration, and CSF detectability. Molecular dynamics simulations confirmed stable binding of VI within the FTO catalytic pocket, consistent with its enzymatic potency and selectivity. In differentiated SH-SY5Y cells, VI protected against Aβ1-42-induced toxicity while increasing global m6A levels and dampening pro-inflammatory gene expression. In SAMP8 mice, chronic oral treatment with VI (3 mg/kg) ameliorated anxiety-like behavior and rescued hippocampal-dependent spatial and recognition memory, concomitant with increased brain m6A and normalization of synaptic and neuroinflammatory markers. Overall, our findings identify compound VI as a selective, brain-penetrant FTO inhibitor with favorable pharmacokinetics and disease-modifying efficacy in a sporadic Alzheimer's disease model, supporting its further development as a neurotherapeutic candidate.

Keywords

Epigenetics; FTO inhibitors; Hit identification; Neurodegeneration; SAMP8; m6A.

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