Oligonucleotide Inhibitors of DNA Methyltransferases

DESCRIPTION (provided by applicant): In this Phase I project Metheor Therapeutics is proposing a unique approach to developing novel DNA methyltransferase (DNMT) inhibitors, testing the concept of a substrate trap designed to capture and deplete the enzyme. Inhibition of DNMT activity is a validated therapeutic approach for Myelodysplastic Syndrome and Acute Myeloid Leukemia. Two nucleoside analogs, Vidaza and Dacogen are marketed for these indications but dose-limiting toxicities due to incorporation in the genome limit their applicationin these indications as well as for other cancers or diseases. The development of novel inhibitors that function without incorporation in the genome has the potential to significantly broaden the clinical use of DNMT inhibitors. In our approach, we merged advances in oligonucleotide chemistry driven by the development of therapeutic RNAi compounds, with the growing understanding of DNMT interaction with oligonucleotide substrates to produce DNMT Trapping Oligonucleotides