Bellver-Sanchís, AinaValle-García, DavidBarbaraci, CarlaRomero-Becerra, FernandoSingh, Rohit KumarJarne-Ferrer, JúliaVasilopoulou, FoteiniIrisarri, AlbaMartínez-Fernández, Carmen (Universitat de Barcelona)Fafián-Labora, J. A.Arufe, M.C.Wüst, CarolinCastellanos, AidaSoto, DavidCasals, NúriaFadó, RutPocock, Jennifer M.Navarro, GemmaVal, CristinaBrea, José M.Loza, María IsabelLleó, AlbertFortea, JuanAlcolea, DanielPérez-Bosque, AnnaMiró, LluïsaPérez, BelénRashid, SajidAli, MuhammadSaqib, ManahilLí Carbó, MarcelGuerrero, AnaVázquez, SantiagoChoudhary, Bhanwar SinghDai, ShaodongEscolano, CarmenFranco, RafaelPallàs, MercéGriñán-Ferré, Christian2026-04-222026-04-222025-12-24Bellver-Sanchis A, Valle-Garcia D, Barbaraci C, Romero-Becerra F, Singh RK, Jarne-Ferrer J, Vasilopoulou F, Irisarri A, Martínez-Fernández C, Fafián-Labora JA, Arufe MC, Wüst C, Castellanos A, Soto D, Casals N, Fadó R, Pocock JM, Navarro G, Val C, Brea J, Loza MI, Lleó A, Fortea J, Alcolea D, Perez-Bosque A, Miró L, Pérez B, Rashid S, Ali M, Saqib M, Lí Carbó M, Guerrero A, Vázquez S, Choudhary BS, Dai S, Escolano C, Franco R, Pallàs M, Griñán-Ferré C. First-in-class SAM-competitive G9a inhibitor FLAV-27 as a disease-modifying therapy for Alzheimer disease. Mol Ther. 2026 Apr 1;34(4):2372-2407.1525-0024https://hdl.handle.net/2183/48058[Abstract] Alzheimer's disease (AD) is characterized by a progressive cognitive decline involving a multifactorial pathophysiology, including epigenetic dysregulation. Here, we report the discovery and preclinical validation of FLAV-27, a first-in-class, S-adenosyl-l-methionine (SAM)-competitive, brain-penetrant, and selective inhibitor of the histone methyltransferase G9a. Unlike prior G9a/GLP inhibitors, FLAV-27 exhibits subnanomolar potency, over 30-fold selectivity, and robust central nervous system bioavailability. Structural studies confirm a unique SAM-binding mode that confers superior specificity and avoids off-target effects. FLAV-27 reduces amyloid beta (Aβ) and p-tau aggregation and restores neuritic complexity in vitro. In Caenorhabditis elegans, it improves mobility, lifespan, and mitochondrial respiration. In mouse models of both late-onset AD (SAMP8) and early-onset AD (5xFAD), FLAV-27 rescues memory performance, social behavior, and synaptic structure. Multi-omics analyses reveal a global reprogramming of H3K9me2/H3K18me-mediated repression, reduced ferroptosis vulnerabilities, and normalization of AD-linked biomarkers, including SMOC1, H3K9me2, and p-Tau181, in the plasma and brain. Our findings position FLAV-27 as a promising epigenetic therapeutic with disease-modifying potential and translational biomarker alignment in AD.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Alzheimer's diseaseG9aSAM-competitive inhibitorSMOC1CognitionEpigeneticsNeuroprotectionTranslationaljournal articleopen access10.1016/J.YMTHE.2025.12.038