Collaboration between University of North Carolina at Chapel Hill and Canadian scientists has resulted in a molecular probe capable of specifically targeting two proteins that affect a wide range of biological functions in humans by controlling the expression of certain genes.

The probe, called UNC0638, is a small molecule created by the researchers that targets the proteins G9a and GLP, which play a role in a variety of conditions from cancer to cocaine addiction. The probe was created in collaboration with the Structural Genomics Consortium based at the University of Toronto and is detailed in a paper published in Nature Chemical Biology.

“This is an excellent chemical probe,” says Jian Jin, PhD, a corresponding author on the study. “We have a great deal of biochemical and cellular data on UNC0638 that shows that it interacts only with the proteins it was meant to and has low toxicity to cells. The combination of high selectivity, robust on-target activity in cells, and low cell toxicity makes UNC0638 a valuable tool for the biomedical community to decipher the role of G9a and GLP in human diseases. Many chemical probes in use today are not as selective.”

Jin is an associate director of medicinal chemistry for the Center for Integrative Chemical Biology and Drug Discovery (CICBDD) at the UNC Eshelman School of Pharmacy.

G9a and GLP are relatively new candidates as drug targets and belong to a class of proteins called epigenetic regulators. The proteins control the expression of genes by specifically modifying the histones around which DNA is packaged.

“Epigenetic regulators are what make liver cells liver cells and brain cells brain cells even though all cells contain the same genetic code,” says Stephen Frye, PhD, one of the paper’s coauthors. “The proteins control what genes are active on a cell-by-cell basis.”

Because G9a and GLP are being eyed as potential drug targets, it is important that a chemical probe be specific, says Frye, who is director of the CICBDD and a research professor at the School. The probe has drug-like properties but is much more specific than some drugs.

“As long as a drug is safe and effective, you don’t necessarily care what the secondary effects might be as long as they are not harmful,” he says. “A probe like UNC0638 has to act cleanly and only interact with proteins it is designed to target. That’s the only way you can be certain that any changes you observe were caused by the probe interacting with its target and not by a peripheral interaction you don’t know about.”

The Structural Genomics Consortium is a public-private partnership promoting the development of new medicines by carrying out basic science of relevance to drug discovery. The core mandate of the SGC is to determine 3D structures of proteins of biomedical importance and proteins that represent potential drug targets. The consortium and its scientists are committed open access and to making their discoveries available without restriction on use. They will not agree to file for patent protection and require the same commitment from any collaborator.

The research team was led by Jin and Cheryl Arrowsmith, PhD, chief scientist of the SGC and a professor at University of Toronto, along with co-first authors Feng Liu, PhD, a postdoctoral research fellow in Jin’s lab at the School; and Masoud Vedadi, PhD, a principal investigator at the SGC, and Dalia Barsyte-Lovejoy, an SGC senior scientist

In addition to Jin, Frye and Liu, the coauthors from UNC-Chapel Hill are Xin Chen; William P. Janzen; Dmitri B Kireev; Jacqueline L Norris; Samantha G. Pattenden; Catherine D. Simpson; and Tim J Wigle of the CICBDD; Thomas J Mangano, Xi-ping Huang, and Bryan L Roth, PhD, of the National Institute of Mental Health Psychoactive Drug Screening Program; and Ashutosh Tripathy of the UNC Macromolecular Interactions Facility.

Coauthors from the SGC are Abdellah Allali-Hassani, Cheryl H Arrowsmith (also with the Ontario Cancer Institute), Peter J Brown, Irene Chau, Aiping Dong, Aled Edwards, Alena Siarheyeva, Wolfram Tempel, and Gregory A. Wasney.

Additional coauthors are Sylvie Rival-Gervier, PhD, of SickKids Hospital in Toronto and INRA of Jouy en Josas, France; Arturas Petronis, MD, PhD, Viviane Labrie, PhD; and Sun-Chong Wang of the Centre for Addiction and Mental Health in Toronto; Peter A. DiMaggio, PhD, and Benjamin A. Garcia, PhD, of Princeton University; James Ellis of SickKids and the University of Toronto.

The project described was funded in part by award number RC1GM090732 from the National Institute of General Medical Sciences, the Carolina Partnership and University Cancer Research Fund from the University of North Carolina at Chapel Hill, the U.S. National Science Foundation, the Ontario Research Fund, the Ontario Ministry of Health and Long-Term Care and the Structural Genomics Consortium.

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