PROJECT SUMMARY Alzheimer’s disease (AD), the most prevalent dementia, has no effective disease-modifying therapeutics. Our recent studies have linked abnormalities in lysine methyltransferases G9a/GLP (also known as EHMT2/1) and histone H3 lysine 9 dimethylation (H3K9me2) to AD pathophysiology. We hypothesize that pharmacological inhibition of G9a and GLP by small molecules can provide a novel and effective therapeutic strategy for the treatment of AD. The objectives of this project are: (a) to demonstrate that newly-discovered G9a/GLP inhibitors are efficacious in AD mouse models; (b) to optimize small-molecule inhibitors of G9a and GLP into a drug candidate. To achieve these goals, we will pursue three specific aims. Aim 1, assess selectivity, cellular activity and in vitro ADME (absorption, distribution, metabolism and excretion) and in vivo pharmacokinetic (PK) properties of lead G9a/GLP inhibitors; Aim 2, evaluate in vivo effects of lead G9a/GLP inhibitors on normalizing behavioral, synaptic, and transcriptional abnormalities in AD mouse models; Aim 3, Optimize current G9a/GLP inhibitor leads into a drug candidate by designing, synthesizing and testing novel compounds to simultaneously optimize potency, selectivity and PK properties. Completion of the proposed studies will not only validate our therapeutic hypothesis, but also generate a drug candidate that could be ultimately translated in the clinic for the treatment of AD. The improved G9a/GLP inhibitors generated in this project will also be invaluable chemical tools for assessing the therapeutic potential of G9a/GLP inhibition in other diseases.