Chordoma is an extremely rare cancer affecting around 1 in 1,000,000 people per year that occurs along the spinal-cord, and currently lacks effective targeted therapies. Brachyury (also known as TBXT) has been identified as the top selectively essential gene in chordoma and is minimally expressed in healthy adult tissues making it a biologically ideal therapeutic target. However, such ligandless transcription factors have traditionally been thought to be difficult to inhibit with small molecules due to their lack of druggable pockets and polar nature of the DNA binding interface. To target brachyury the team initially determined structures of brachyury bound to DNA and were able to produce APO form crystals that diffracted to high resolution, enabling crystallographic fragment screening. The team were able to progress the fragments from binders that were undetectable in a biophysical assay to a chemical series of potent binders (Kd 10-20 µM). The work is now published in Nature Communications -Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy