Jenna Fernandez graduated from Macalester College in Saint Paul, MN with a B.A. in Chemistry in May 2014. While at Macalester, Jenna did computational research of atmospheric reaction mechanisms in the lab of Dr. Keith Kuwata. Jenna is currently a third year graduate student in the Tretyakova research group at the University of Minnesota—Department of Medicinal Chemistry. The Tretyakova Lab studies epigenetic alterations such as abberant cytosine methylation and hydroxymethylation and their role in the development of lung cancer. Jenna’s work focuses on the TET enzymes that oxidize methylcytosine to remove methylation marks. She is currently working to identify direct and selective inhibitors of TET proteins to elucidate their roles in human disease and to develop epigenetic modulators as new therapeutic agents. In her free time, Jenna enjoys hiking with her dog, running, and cooking.
Development of First Specific Inhibitors of Ten-Eleven Translocation (TET) Proteins
as Biological Probes and Potential Epigenetic Modulators
5-Methylcytosine (mC) is a stable epigenetic modification of DNA that plays a key role in controlling gene expression. Human tumors are characterized by large alterations in cytosine methylation patterns, leading to unregulated expression of transforming oncogenes and silencing of tumor suppressor genes. A family of ten-eleven translocation (TET) proteins (TET1-3) induce oxidation of 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC) and 5-carboxylcytosine (caC). fC and caC are excised by thymine DNA glycosylase (TDG) and are replaced with C via base excision repair, thus mC oxidation can result in active demethylation and gene re-activation.
By oxidizing mC and removing the methylation marks, TET proteins play a key role in a number of biological processes and have been implicated in many diseases including cancer and autism. However, no Tet-specific inhibitors have been developed thus far. N-oxalylglycine (NOG), an α-ketoglutarate analogue, inhibits all three Tet proteins; however, it also inhibits other Fe(II)/α-ketoglutarate dependent enzymes. This lack of selectivity does not allow NOG to serve as a useful chemical tool. Our lab is working to identify direct and selective inhibitors of Tet proteins to elucidate their roles in human disease. Compounds showing high inhibitory activity will be utilized to develop structurally diverse analogs.
In the present work, a computational screen was completed using the National Cancer Institute (NCI) Diversity Set IV to identify potential inhibitors of TET proteins. Additionally, virtual hits are then assessed in a kinetic HPLC-ESI-MS/MS assay to probe their effect on TET mediated oxidation of mC to hmC. Compounds showing high inhibitory activity will be utilized to develop structurally diverse analogs to create potent and selective inhibitors of TET proteins.