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School Researchers Discover First-in-Class Chemical Probe

School Researchers Discover First-in-Class Chemical Probe

Lindsey James, PhD, and the UNC1215 chemical probe

03/07/2013

A team of scientists led by researchers at the UNC Eshelman School of Pharmacy have discovered a first-in-class chemical probe that will give researchers a powerful tool to investigate the function of malignant brain tumor domains in biology and disease.

The discovery is discussed in the cover story of the March 2013 issue of Nature Chemical Biology. Lindsey James, PhD, a research assistant professor at the School, is the first author for the article. Stephen Frye, a Fred Eshelman Distinguished Professor at the School and director of the School’s Center for Integrative Chemical Biology and Drug Discovery, is one of the corresponding authors.

The probe, named UNC1215, targets the L3MBTL3 methyl-lysine reader domain. Domains are structural and functional units within proteins, and they are usually responsible for a particular function or interaction. L3MBTL3 mediates interactions between proteins, which have historically been difficult to target with small, drug-like molecules.

“Many people believe that protein-protein interactions are difficult to target,” James says. “Often they have a large surface area, so it is hard for small molecules to go in and intervene.”

UNC1215, the researchers say, is the first known chemical probe for a methyl-lysine-reader domain. Protein methylation dynamics, James says, have been shown to play an important role in a number of biological processes. In addition, aberrant methylation levels are one mechanism by which those processes can contribute to disease.

“High-quality, potent, and selective chemical probes of methyl-lysine reader domains will serve as excellent tools in improving our understanding of their targets,” James says. “Before UNC1215, there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first-in-class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets.”

Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development and has pointed to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to observe the overall effect of their perturbation on the disease state.

Frye’s lab will provide UNC1215 to researchers free of charge on request, and the probe is already available through commercial vendors as well.

This research was supported by NIH grants (RC1GM090732 and R01GM100919) and the University Cancer Research Fund.

— Story courtesy of the UNC Lineberger Comprehensive Cancer Center

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