The stabilization of long-term memory requires the activity of DNA methyltransferases (DNMTs), which methylate plasticity-regulatory genes. Reducing DNA methylation through the inhibition of DNMT, is sufficient to impair long term memory. These methyl groups on the DNA can be removed through the activity of the ten-eleven translocation (TET) family of enzymes. The genetic deletion of TET enzymes in mice has been shown to increase DNA methylation and improve memory, both associative and spatial. Here, an approach is being taken to design, synthesize, and evaluate therapeutic compounds that increase the fidelity of DNA methylation by inhibiting TET enzymes. A library of first generation inhibitors was synthesized, of which some demonstrated inhibitory activity at low micromolar concentrations. Following these results, computational modeling using Molecular Operating Environment (MOE) software was used to identify specific molecular interactions within the TET enzyme binding site, based of the crystal structure of TET2 bound to methylated DNA and homology models of the other TET enzymes. The data collected by this in silico analysis, as well as the activity of first generation compound Bobcat339, have led to the development of second generation inhibitors. Paralleling this research, in vitro testing was conducted in order to determine the efficacy of this library in mouse hippocampal neuronal cell culture. Ultimately, producing a successful TET inhibitor could result in wide-ranging therapeutic applications for diseases and disorders associated with epigenetic dysregulation, including disorders of memory function.

Cytosine-based TET enzyme inhibitors

2019 Spring National Meeting

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