FLAV-27 is a potent, selective, SAM-competitive, brain-penetrant inhibitor of histone methyltransferase G9a with IC50 of 0.6 nM, with excellent selectivity over GLP (3.2% inhibition at 1 uM).
FLAV-27 demonstrates high selectivity for G9a, showing less than 15% inhibition at 1 μM across a panel of 32 HMTs, including H3K9 (SUV39H1, SUV39H2, and SUV420H1), H3K27 (enhancer of zeste homolog 2 (EZH2)), H3K4 (SET domain containing 7 (SETD7) and mixed lineage leukemia (MLL)), H3K79 (disruptor of telomeric silencing 1-like (DOT1L)), and H4K20 (SETD8), as well as various protein arginine methyltransferases (PRMTs).
FLAV-27 exhibits robust central nervous system bioavailability.
FLAV-27 reduces amyloid beta (Aβ) and p-tau aggregation and restores neuritic complexity in vitro.
FLAV-27 improves mobility, lifespan, and mitochondrial respiration in Caenorhabditis elegans.
FLAV-27 rescues memory performance, social behavior, and synaptic structure in mouse models of both late-onset AD (SAMP8) and early-onset AD (5xFAD).