Transition State Analogues as Modulators of DNA Methylation

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DESCRIPTION (provided by applicant): Transition state analogue design is a frontier technology for targeting specific enzymes in human disease. MT-DADMe-Immucillin-A is an orally available transition state analogue inhibitor for human 5'- methylthioadenosine phosphorylase (MTAP). MTAP inhibition slows or prevents the growth of human head and neck, prostate and human lung cancers in mouse xenografts. Normal tissues are not affected and the inhibitor shows no toxicity against normal cells or to mice. The MTAP inhibitor alters metabolites that are expected to change the ability of DNA methyltransferases to methylate DNA. Cancers are commonly caused by mutations that change gene expression patterns and permit the growth and metastases of tumors. Gene expression patterns leading to cancer are governed, in part, by DNA methylation at regions of the genome rich in CpG bases, called CpG islands. The hypothesis for this research is that MTAP inhibitors alter metabolite levels in cancer tissues to inhibit DNA methylation patterns in humans. Loss of methylation for some of the CpG islands near cancer suppression genes is proposed to alter the gene expression patterns of the cancer cells and to slow or prevent cancer cell growth. This hypothesis will be explored in cultured cell lines and mouse xenograft models of the major human malignancies, lung, breast, prostate colon, head and neck and cervical cancers. Results of tumor growth in mouse xenografts will determine if orally available MTAP inhibitors are effective at suppression of the major human cancers and will identify the altered gene expression patterns. The hypothesis also proposes that inhibition of DNA methylation at CpG islands is mediated through DNA methytransferases. Assays of the human methyltransferases in living cultured cancer cells, cell extracts and in purified complexes of human DNA methyltransferases will be coordinated with DNA methylation patterns and gene expression arrays. New MTAP inhibitors will be synthesized to improve efficacy, oral availability and chemical stability. PUBLIC HEALTH RELEVANCE:Human cancers result from loss of control of the DNA regions that act as regulators for cell division. New drug candidates are being developed to restore normal control to these cell regulators. The drugs are then tested to see if they prevent human cancers from growing in cultured human cells and in mice. If successful, these studies could lead to new orally available and non-toxic drugs to treat cancers in humans.