Active DNA methylation in neurons that encode experiential learning is required for the formation of long-term memory. The Tet family of enzymes are known to remove DNA methylation by detecting 5-methylcytosine and facilitating their oxidative removal via an Fe(II)/alpha-ketoglutarate-dependent mechanism. We hypothesized that learning causes long-term changes in gene expression in the hippocampus and facilitates long-term memory, because of active DNA methylation changes at plasticity-related genes. To test this idea, we sought tools to increase DNA methylation fidelity by inhibiting the function of the Tet enzymes; however, there currently does not exist sufficiently potent Tet enzyme inhibitors to serve as probes of memory function. Here, we describe the <i>de novo</i> design, synthesis, and evaluation of Tet enzyme inhibitors. Using a combination of computational and traditional QSAR approaches we have developed small molecule inhibitors of the Tet enzymes in the sub-micromolar range. Combined with proof of principle data acquired from the use of constitutive and conditional Tet enzyme knockout mice in spatial memory tasks, these small molecule inhibitors of the Tet enzymes may serve as therapeutics to enhance memory function in disease and disorders of memory.<br/>

Designing tet enzyme inhibitors to enhance learning and memory

255th National Meeting (2018)

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