Uncovering and targeting brachyury’s hidden, druggable hotspots
Like a key nestling comfortably into the lock it was made for, a conventional drug must be able to fit into a specific pocket within the protein it targets. Unfortunately, more than 80% of human proteins — including brachyury, the key driver of chordoma — do not have obvious pockets to target. To drug these historically “undruggable” proteins, scientists are turning to new, cutting-edge techniques.
One such promising approach is underway in the laboratory of Dr. Daniel Nomura at the University of California, Berkeley. It involves the use of an innovative technology called activity-based protein profiling (ABPP), which uses chemical probes to map reactive sites within a protein that might not be apparent based on its structure alone. With ABPP, the team has already identified several such “hotspots” on the brachyury protein.
Building on this success, Dr. Nomura’s team is now using novel chemistry techniques to rapidly discover molecules that bind strongly and irreversibly to these newly discovered brachyury hotspots. The molecules they uncover may be able to inhibit the function of brachyury, providing an immediate foothold for constructing drugs against brachyury. Alternatively, if the scientists identify molecules that can bind to brachyury but cannot change its function, they can attempt to use the compounds to create drugs that leverage the cell’s natural protein clean-up machinery to degrade brachyury.
This work is being performed in the context of a broader ASPIRE project funded in the Nomura Lab by The Mark Foundation for Cancer Research to target “undruggable” proteins implicated in cancer. A world-renowned chemical biologist, Dr. Nomura has used ABPP to discover more than 100,000 druggable hotspots across tens of thousands of protein targets previously thought to be undruggable.
Why this project matters
Discovering a chemical compound that can bind to brachyury will serve as a starting point for developing therapies that inhibit or degrade this protein, known to be the Achilles’ heel of chordoma. Brachyury also plays a role in metastasis in many cancers, so discoveries from this project could yield new treatments that are likely to have an impact far beyond chordoma.
Funding and support
- Therapeutic Innovation Award from The Chordoma Foundation and The Mark Foundation for Cancer Research
- Access to chordoma cell lines
Brachyury Drug Discovery