First-in-Class SAM-Competitive G9a Inhibitor FLAV-27 as a Disease-Modifying Therapy for Alzheimer’s Disease
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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, 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.