Bivalent degraders of the understudied transcription factor TBXT for the rare cancer chordoma

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Project Summary / Abstract Chordoma is a rare bone cancer with an incidence of about 1 in a million people. The tumors can appear anywhere along the spine, from the tailbone to the skull base. The only available treatments are radiation and surgery, and surgery can be complicated due to adjacency to important and sensitive areas like the brain and spinal cord. No medicines are approved for the treatment of chordoma and, as such, identification of druggable targets is a critical unmet need. The understudied protein brachyury, gene name TBXT, is upregulated in chordoma and is both a key driver and potential therapeutic vulnerability of chordoma. Brachyury is expressed at very low levels or not at all in most human tissues, providing confidence that compounds that modulate brachyury will safely target the cancer and have an excellent therapeutic window in humans. Brachyury (TBXT) is a transcription factor, a class of proteins often considered undruggable. We have recently identified small molecule ligands that bind to brachyury, paving the way for a new approach to target this protein using bivalent degrader molecules. Bivalent degraders, often called proteolysis targeting chimeras (PROTACs) harness the power of the ubiquitin-proteasome system to label proteins for degradation and this leads to their removal. In this pilot project, we will convert our small molecule brachyury ligands into a library of PROTAC reagents and evaluate their ability to degrade brachyury in chordoma cell lines. To improve our chances of successful degradation we will vary the brachyury ligand, the linker, and the E3 ligase targeting moiety. Successful completion of this project will establish the understudied protein brachyury as a druggable target for chordoma and set the stage for larger projects designed to identify PROTACs that can be used to treat this devastating rare cancer.