The Target Enabling Packages (TEPs) Programme continues to elucidate and enable novel targets for drug development. We are delighted to present our TEP for the embryonic transcription factor T-box transcription factor T (TBXT), the homologue of mouse Brachyury. Recent studies indicate that expression of TBXT is essential for persistence and growth of Chordoma, a rare cancer occurring along the spinal cord. 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 to identify 29 fragments bound in 6 clusters. The crystal structures of the bound fragments provide starting points for medicinal chemistry campaigns to identify and develop binders which could be used to disrupt TBXT activity or to induce the degradation of the protein.
Structures of WT (red/orange, PDB: 6F58) and G177D variant (blue/cyan, PDB: 6F59) in complex with DNA. The proteins bind to the palindromic DNA sequence as homodimers. The position of the variant residue G/D 177 is marked (*).