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A powerful new biochemical platform is feeding the study of a family of enzymes that are promising targets for the treatment of cancer.
Posted today in Progress of scienceThe new method provides a high-resolution view of how these enzymes, called lysine methyltransferases, selectively label proteins with chemical labels that alter their function. Because of their central role in all aspects of health and disease, proteins and the molecules that modify and interact with them are often targets for therapeutic development.
The platform was developed by Scott Rothbart, Ph.D., of the Van Andel Research Institute, in collaboration with EpiCypher, Inc.
"This technology helps us to determine the protein interaction networks for this family of little-studied enzymes based on chemical labeling," Rothbart said. "Several inhibitors of these enzymes are currently under clinical development for cancer treatment, and defining the spectrum of their activity is critical to understanding exactly how these drugs work and to selecting reliable biomarkers to track their activity in patients."
Humans have about 20,000 genes containing the instructions for making proteins, molecular work tools responsible for carrying out all the processes of the human body, from digesting food to managing communication between cells.
Once a protein is built, its function is often changed by the addition of small chemical labels, which tell proteins where to go in the cell and when to do their work. There are more than 100 different types of these labels, including the addition of methyl groups to the amino acid lysine.
Using their new technique, the team discovered that methylation of lysine could score much more protein than previously thought.
"Our study suggests that what we currently know about lysine methylation is only the tip of the iceberg," said Evan Cornett, Ph.D., the first author of the lysine. study and postdoctoral fellow in the Rothbart laboratory at the Institute. "The method we have developed will allow us to identify new targets among all lysine methyltransferases in humans and, in doing so, will help us and others to determine which cancers and other diseases could benefit from treatments targeting this clbad of enzymes. "
This technology is the latest breakthrough from a collaboration between Rothbart Lab and EpiCypher. Their work has been supported by several SBIR (Small Business Innovation Research) awards from the National Institutes of Health (NIH). Commonly called the US Seed Fund, SBIR provides federally funded research grants to small businesses in order to invest in discoveries led by Americans. The SBIR program supports small businesses in the biotechnology sector, with a focus on strategies with significant potential for significant impact and successful commercialization in the medical field. SBIR grants advocate for strengthened partnerships between academia and industry to bridge the gap between basic science and clinical progress, and are an important driver of technological innovation.
"The beauty of this technology lies in its simplicity and throughput, which is astounding compared to current mbad spectrometry approaches," said Martis Cowles, Ph.D., Business Director at EpiCypher and co-author of the study. "We are excited to use this technology to help drug developers identify new therapeutic targets and even identify the optimal target substrates for screening of high-throughput inhibitors."
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