Can neurodegenerative conditions be effectively treated by only changing the behavior of cells in the brain? That is an interesting question, particularly given the sizable research focus placed on epigenetic reprogramming in recent years. On the one hand there are clearly issues that occur outside cells, such as formation of aggregates or chemical changes in the extracellular matrix. There are other issues inside cells that no amount of altered cell behavior can fix, such as mutational damage to nuclear DNA. On the other hand, a variety of approaches that focus on altering epigenetic control of nuclear DNA structure and gene expression have led to improved function in animal models of neurodegenerative conditions, such as the example shown here.
Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of neurodegenerative diseases. Unlike irreversible genetic mutations, epigenetic marks such as histone methylation are dynamic and potentially reversible, making them attractive therapeutic targets. In particular, two histone methyltransferases (HMTs), GLP (EHMT1) and G9a (EHMT2), have attracted increasing attention due to their role in catalyzing the dimethylation of histone H3 at lysine 9 (H3K9me2), a repressive mark associated with transcriptional silencing. G9a/GLP-mediated epigenetic repression has been shown to influence critical processes such as neuronal development, synaptic plasticity, and memory consolidation.
Intriguingly, an aberrant upregulation of G9a activity has been linked to increased oxidative stress, neuroinflammation, and neuronal dysfunction, which are hallmarks of Alzheimer's disease (AD) and other neurodegenerative conditions. However, translating G9a inhibition into a viable therapeutic strategy has proven to be difficult. Most known G9a inhibitors, including BIX-01294, UNC0638, and A-366, suffer from poor selectivity, high cytotoxicity, and inadequate blood-brain barrier (BBB) permeability, which are limitations that are less critical in oncology but represent major obstacles for central nervous system (CNS) applications. Consequently, the therapeutic potential of G9a inhibition in neurodegeneration remains largely untapped.
Here, we report the discovery and characterization of FLAV-27, a brain-penetrant, subnanomolar inhibitor of G9a with exceptional selectivity for G9a over the closely related GLP and other methyltransferases. Unlike previously reported G9a inhibitors, FLAV-27 exhibits favorable CNS drug-like properties, including excellent BBB permeability and a strong safety profile. FLAV-27 reduces amyloid beta (Aβ) and phosphorylated 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.
Link: https://doi.org/10.1016/j.ymthe.2025.12.038
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