GRAND RAPIDS, Mich. (Nov. 28, 2018) -- A powerful new biochemical platform is fueling the study of a family of enzymes that are promising targets for cancer treatment.
Published today in Science Advances, the new method provides a high-resolution view of how these enzymes, called lysine methyltransferases, selectively mark proteins with chemical tags that alter their function. Because of their central role in all aspects of health and disease, proteins and the molecules that edit and interact with them often are targets for therapeutic development.
"This technology helps us to determine protein interaction networks for this understudied enzyme family based on chemical tagging," said Rothbart. "Several inhibitors of these enzymes are currently in the clinical development pipeline for cancer therapy. Defining the spectrum of their activity is critical for understanding exactly how these drugs work and for selecting reliable biomarkers to track their activity in patients."
Humans have approximately 20,000 genes that contain the instructions for making proteins, the molecular workhorses that are responsible for carrying out every process in the human body, from aiding in food digestion to managing communication between cells.
Once a protein is constructed, its function is often modified by the addition of small chemical tags, which instruct proteins where to go in the cell and when to perform their job. There are more than 100 different types of these tags, including the addition of methyl groups to the amino acid lysine.
Using their new technique, the team found that many more proteins may be tagged by lysine methylation than previously thought.
"Our study suggests that what we currently know about lysine methylation is just the tip of the iceberg," said Evan Cornett, Ph.D., the study's first author and a postdoctoral fellow in Rothbart's laboratory at the Institute. "The method we developed will allow us to identify new targets across the full set of lysine methyltransferases in humans and, in doing so, help us and others determine which cancers and other diseases could benefit from treatments targeting this class of enzymes."
This technology is the latest advance stemming from a collaboration between Rothbart's lab and EpiCypher. Their work was supported by several National Institutes of Health (NIH) Small Business Innovation Research (SBIR) awards. Commonly known as America's Seed Fund, SBIR provides federally funded research grants to small businesses in an effort to invest in American-led discovery. The SBIR program supports small businesses in the biotechnology sector, with a focus on strategies that have a high potential for significant impact and successful commercialization in the medical field. SBIR grants advocate for increased academic-industry partnerships to bridge the gap between basic science and clinical advancements, and are important stimulators of technological innovation.
"The beauty of this technology is its simplicity and throughput, which is staggering compared to current mass spectrometry-based approaches," said Martis Cowles, Ph.D., EpiCypher's Chief Business Officer and study co-author. "We are excited to use this technology to help drug developers identify new therapeutic targets and even identify optimal target substrates for high-throughput inhibitor screening."
In addition to Rothbart, Cornett and Cowles, authors include Bradley M. Dickson, Ph.D, Robert M. Vaughan, Kevin M. Shaw and Philip P. Versluis, of Van Andel Research Institute; Krzysztof Krajewski, Ph.D., of University of North Carolina at Chapel Hill; Nicholas Spellmon, Ph.D., and Zhe Yang, Ph.D., of Wayne State University School of Medicine; Andrew Umstead and Irving E. Vega, Ph.D., of Michigan State University; Zu-Wen Sun, Ph.D., of EpiCypher; and Joseph Brunzelle, Ph.D., of Argonne National Laboratory.
Research reported in this publication was supported by Van Andel Research Institute and the National Institute of General Medical Sciences of the National Institutes of Health under award numbers R35GM124736 (Rothbart), R43GM110869 (Sun) and R44GM112234 (Sun). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health.
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Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 400 scientists, educators and staff. Van Andel Research Institute (VARI), VAI's research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson's and other diseases and translating those findings into effective therapies. The Institute's scientists work in onsite laboratories and participate in collaborative partnerships that span the globe. Learn more by visiting vari.vai.org. 100% To Research, Discovery & Hope®
A pioneer in the field of epigenetics and chromatin biology, EpiCypher® is a biotechnology company developing transformative technologies for researchers and drug developers worldwide. EpiCypher manufactures and sells a series of products and assay platforms that use recombinant "designer" modified nucleosomes (dNucs), including the SNAP-ChIP® product family for quantitative ChIP applications and the EpiDyne® product family for nucleosome remodeling assays, as well as recombinant histone binding proteins and enzymes, peptides and antibodies, and offers a broad range of custom substrate manufacturing and assay development services.