The term “molecular glue degraders” may sound like the next K-pop band, but inside the lab of biochemist Thomas Kodadek, Ph.D., scientists are rocking MGDs for a serious purpose: finding treatment options for people with incurable diseases, including aggressive cancers and brain diseases.
Their goal is to exploit cells’ own internal recycling systems to address these otherwise “undruggable” diseases. A new grant from Europe is accelerating that work.
Kodadek’s team at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology recently won a worldwide competition to collaborate with the research and development department of the health care business sector within Merck KGaA, Darmstadt, Germany. Kodadek’s proposal was selected from a large number of applications globally. The award provides the Kodadek laboratory with a three-year grant worth about $350,000. It also provides access to the science and technology company’s extensive infrastructure and drug development expertise.
Kodadek said molecular glue degraders, or MGDs, are an exciting new frontier in drug discovery. They are small molecules able to glue together unrelated molecules in the cell, specifically a disease-causing molecule such as a mutated protein, and an enzyme that tags cellular waste for recycling. The MGDs thus trigger the destruction of the disease target.
“The goal is ultrapotent and long-lasting inhibition of the disease target’s activity,” said Kodadek, who is a member of the UF Health Cancer Institute.
Despite rapid advances in drug discovery, genomics and proteomic research, thousands of diseases still lack treatments due to the structure or inaccessibility of their target proteins. These disease targets have earned the nickname “undruggable.” They include much-studied proteins such as PTP1B, a gene linked to metabolic diseases, including diabetes. Short for “protein-tyrosine phosphatase 1B,” it makes an enzyme able to regulate insulin sensitivity, appetite and cell proliferation, a cancer driver.
Scientists have tried unsuccessfully for decades to make an inhibitor to treat diabetes. Kodadek believes the molecular glue strategy of tagging the protein for destruction might succeed where more direct approaches have failed.
Finding the unique, precise molecules able to act as molecular glues poses many complex scientific and technical challenges, Kodadek said. Recognizing this, the Merck KGaA, Darmstadt, Germany competition focused on identifying new chemical screening methods that can reliably identify MGDs from a large collection of chemical compounds.
The Kodadek laboratory’s winning entry is based on work recently published in the Journal of the American Chemical Society. Kodadek’s group created a collection of millions of chemical compounds linked to the surface of microscopic beads. The treated beads are incubated with enzymes that can tag items for recycling in a cellular machine called a proteasome.
Characterization of the structure of the tagging compound provides a potential drug lead, or starting point.
The initial development of the drug discovery platform was supported, in part, by a philanthropic contribution of the Klorfine Foundation and a grant from the National Institutes of Health (R35 GM151875).
“We are in the early days of the development of this technology,” said Kodadek, chemistry professor and principal investigator on the project. “Initial indications are that it has enormous potential to speed the discovery of these potentially game-changing molecular glues.”