Funding will enable continued development of molecular glues as a tool to enable degradation of misshapen proteins
Seattle, WA – February 5, 2025
Washington Research Foundation (WRF) has awarded a $275,000 technology commercialization grant to a team led by Baiyun Wang, Ph.D., a postdoctoral fellow in Dr. Ning Zheng’s lab at the University of Washington’s (UW) Department of Pharmacology. WRF supported earlier proof-of-concept work on this research with a $100,000 grant in 2023.
When proteins become defective or accumulate in excess, cells have a process for breaking them down. In this process, a mediator protein attaches a molecule called ubiquitin to the rogue protein, marking it for degradation. However, mutations can prevent some defective proteins from binding to the mediator, allowing them to evade ubiquitin tagging and build up in the cell. This accumulation is linked to certain cancers, making it an important target for therapeutic intervention. Traditional small-molecule drugs can inactivate these proteins by binding to their active sites, but some proteins lack accessible active sites, making them “undruggable” by conventional methods.
Molecular glue degraders, a new treatment approach largely pioneered in the Zheng lab, offer an innovative solution to this challenge. Rather than blocking a protein’s active site, these small molecules restore the interaction between mutant proteins and ubiquitin-tagging mediator proteins, effectively “gluing” them together to enable tagging and degradation of the faulty protein. This strategy not only makes previously undruggable proteins accessible to treatment but also allows for precise targeting of misshapen proteins, minimizing the degradation of healthy proteins and reducing potential side effects.
Wang’s team is developing a novel platform for identifying new molecular glue degraders to target proteins known to be associated with cancer. Once researchers have a target protein, they first search a set of known ubiquitin mediator proteins to find any that may have a weak binding affinity with the target protein. Starting with these weak binders, they then perform robust compound screening assays to identify molecules that can act as molecular glues between the selected mediator and the protein. As a proof-of-concept, researchers have already used this pipeline to find a set of molecular glues targeting NRF2 and β-catenin. The accumulation of either of these proteins in cells has been associated with cancer and both are undruggable by standard small molecules.
With this funding, Wang and her colleagues will continue to advance their molecular glue research that targets NRF2 and β-catenin, identifying which of their set of possible molecules would be most effective in a therapeutic context. They will additionally continue refining their molecule glue discovery pipeline.
Wang is excited about the potential of this new discovery pipeline. “Molecular glue degraders offer exceptional advantages over conventional small molecule drugs and other types of protein degraders. However, the rational discovery of these powerful compounds remains a significant challenge. With support from WRF, we aim to build a scalable platform for molecular glue discovery, with a focus on oncology targets long considered undruggable.”
Meher Antia, Ph.D., WRF’s director of grant programs, said, “We are delighted to continue supporting the discovery of molecular glue degraders by Baiyun and her team. Their rational approach to identifying compounds offers the possibility of successfully targeting proteins in a way that has not been previously possible. WRF funds will be used to de-risk a novel approach, which is a major goal of our technology commercialization grant program.”
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About Washington Research Foundation
Washington Research Foundation (WRF) supports research and scholarship in Washington state, with a focus on life sciences and enabling technologies.
WRF was founded in 1981 to assist universities and other nonprofit research institutions in Washington with the commercialization and licensing of their technologies. WRF is one of the foremost technology transfer and grant-making organizations in the nation, having earned more than $445 million in licensing revenue for the University of Washington and providing over $169 million in grants to the state’s research institutions to date.
WRF Capital, the investment vehicle for Washington Research Foundation, has backed 132 local startups since 1996. Returns support the Foundation’s investment and grantmaking programs.
