Human T-box transcription factor T (Brachyury); A Target Enabling Package

Chordoma is a rare cancer occurring along the spinal cord (OMIM: 215400). Chordoma is derived from an embryonic tissue, the notochord, and over-expresses the embryonic transcription factor T-box transcription factor T, the homologue of mouse Brachyury. Chordomas are “genomicaly silent” cancers that do not carry an extensive mutation load. Recent studies indicate that expression of TBXT is essential for persistence and growth of chordoma cells. As TBXT is not expressed in any post-embryonic tissues, it could be an excellent target for treatment of chordoma. The long-term aim of this project is to test whether TBXT can be targeted with small molecules with sufficient affinity and specificity to be therapeutically useful. In this TEP we have determined crystal structures of the DNA-binding domain (DBD) of TBXT with and without cognate DNA oligonucleotides. The DNA-free protein crystals were used in a high-throughput fragment screen to identify 29 fragments bound in 6 clusters. The crystal structures of the bound fragments provide starting points for development of stronger binders which could be used to disrupt TBXT activity or to induce the degradation of the protein through a Proteolysis-targeting chimeric molecule (PROTAC) approach.