Methyltransferases are a class of enzymes that install a methyl (-CH3) substituent onto a variety of cellular substrates. Such methylation events, when decorating DNA or DNA-associated proteins (such as histones), are known to control gene transcription. Dysregulated methylation patterns (often resulting from over- or underexpressed methyltransferase enzymes) play a key role in silencing anti-apoptotic genes and activating pro- tumorigenic ones, leading to uncontrolled cellular growth, commonly known as cancer. Despite their relevance in disease, selective and cell-active inhibitors are currently available for only a handful of the ~150+ human methyltransferases. We hope to address this shortcoming by developing a universal chemoproteomic platform for profiling methyltransferase activity and inhibition in human cells and proteomes. To accomplish this goal, we have synthesized a small library of photoaffinity probes that target the cofactor binding site of methyltransferases. Using these probes, we will functionally characterize methyltransferases in a variety of normal and cancerous tissues, in an attempt to discover novel associations between methyltransferases and cancer. Second, by exploiting a recently discovered lead inhibitor of the cancer-associated enzyme NNMT, we will pursue the development of a selective and in-vivo active inhibitor of NNMT. We will further pursue selective covalent inhibitors for several cancer-associated methyltransferases. This work has the potential to change our understanding of the underlying molecular drivers of cancer pathogenesis, and will hopefully be translatable to eventual clinical applications.

Public Health Relevance

Methyltransferases are a class of enzymes that are able to control gene expression through a variety of mechanisms;dysregulation of these genes can lead to cancer. The goal of this project is to explore these cancer-related enzymes, and build tools to determine their specific roles in cancer. This work has the potential to further our understanding of the mechanistic underpinnings of epigenetic gene control.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA186587-01
Application #
8717396
Study Section
Special Emphasis Panel (ZRG1-F04-W (20))
Program Officer
Jakowlew, Sonia B
Project Start
2014-06-16
Project End
2017-06-15
Budget Start
2014-06-16
Budget End
2015-06-15
Support Year
1
Fiscal Year
2014
Total Cost
$53,282
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037