FTO-IN-17 is an orally active and brain-penetrant FTO (m 6 A RNA demethylase) inhibitor with an IC50 of 1.1 μM. FTO-IN-17 stably binds the FTO catalytic pocket. FTO-IN-17 protects against Aβ1-42-induced toxicity while increasing global m 6 A levels and dampening pro-inflammatory gene ( CXCL10, TNF-α ) expression. FTO-IN-17 ameliorates anxiety-like behavior and rescues hippocampal-dependent spatial, recognition memory and neuroinflammation in Alzheimer's disease mice models [1].
In Vivo, FTO-IN-17 (3 mg/kg; I.g.,; daily; 28 days) ameliorates anxiety-like behavior and rescues spatial and recognition memory deficits in Alzheimer's disease mice models, concomitant with increased brain m6A levels, normalized synaptic plasticity markers, and reduced neuroinflammation[1].
In Vitro, FTO-IN-17 (Compound VI) exhibits high in vitro blood-brain barrier permeability (Pe = 12.2 × 10-6 cm/s)[1]. FTO-IN-17 (0.01-50 μM; overnight) potently inhibits human FTO demethylase activity with an IC50 of 1.1 μM[1]. FTO-IN-17 (10 μM; overnight) is fully selective for human FTO over human ALKBH5 demethylase, showing no inhibition of ALKBH5 at 10 μM[1]. The (S)-stereoisomer of FTO-IN-17 exhibits significantly stronger, more stable binding to human FTO than the (R)-stereoisomer, with over 7 times higher calculated binding affinity[1]. FTO-IN-17 (0.001-50 μM; 30 min pre-incubation + 24 h co-incubation) provides sustained, dose-dependent neuroprotection against Aβ1-42-induced toxicity in differentiated SH-SY5Y cells, increases global m6A levels, and downregulates pro-inflammatory gene expression at 1 μM[1].
References:
[1]. Irisarri A, et al. 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;312:118852.
In Vivo, FTO-IN-17 (3 mg/kg; I.g.,; daily; 28 days) ameliorates anxiety-like behavior and rescues spatial and recognition memory deficits in Alzheimer's disease mice models, concomitant with increased brain m6A levels, normalized synaptic plasticity markers, and reduced neuroinflammation[1].
In Vitro, FTO-IN-17 (Compound VI) exhibits high in vitro blood-brain barrier permeability (Pe = 12.2 × 10-6 cm/s)[1]. FTO-IN-17 (0.01-50 μM; overnight) potently inhibits human FTO demethylase activity with an IC50 of 1.1 μM[1]. FTO-IN-17 (10 μM; overnight) is fully selective for human FTO over human ALKBH5 demethylase, showing no inhibition of ALKBH5 at 10 μM[1]. The (S)-stereoisomer of FTO-IN-17 exhibits significantly stronger, more stable binding to human FTO than the (R)-stereoisomer, with over 7 times higher calculated binding affinity[1]. FTO-IN-17 (0.001-50 μM; 30 min pre-incubation + 24 h co-incubation) provides sustained, dose-dependent neuroprotection against Aβ1-42-induced toxicity in differentiated SH-SY5Y cells, increases global m6A levels, and downregulates pro-inflammatory gene expression at 1 μM[1].
References:
[1]. Irisarri A, et al. 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;312:118852.