We propose to develop a new class of anticancer therapeutics based on inhibiting DNA cytosine methyltransferase (DNMT). Such compounds will form the basis for subsequent drug development, with potential applications to cancer therapy. DNA methylation plays an essential role in regulating gene expression; inhibiting the enzyme is a validated anticancer strategy. Sporadic forms of cancer have an epigenetic component, which are amenable to reversible intervention; thus are inherently less cytotoxic. We have developed an enzyme-based high throughput screen and identified small molecule DNMT inhibitors in an initial 8,000 compound screen. We have purchased a 50,000 compound library, and from this historical library will be submitted to a secondary cell-based screen to detect inhibition of methylation of a promoter containing a green fluorescence protein (GFP) reporter. Lead compounds will be tested in cell-based assays to determine their ability to alter the methylation pattern and expression of specific genes, in which hypermethylation has been suggested to play a role in tumorigenesis. The best candidates will be submitted to a panel of cytotoxicity studies and used as a design platform for the synthesis of new compounds. We expect to develop small molecule inhibitors with acceptable efficacy and toxicity profiles for testing in animal models of human cancers.
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