Aberrant expression of the transcription factor Brachyury (also known as TBXT) drives the growth of chordoma, a rare bone cancer with limited treatment options. While transcription factors are traditionally considered undruggable by small molecules, advances in DNA-encoded library (DEL) screening and data-driven drug discovery technologies are challenging this conventional wisdom. To discover noncovalent small molecule ligands for Brachyury, we screened X-Chem’s DEL deck comprising >150 billion diverse compounds against the Brachyury DNA-binding domain. The screen produced a rich dataset where ~73k compounds, representing 960 distinct chemical families, showed positive enrichment signal. Using X-Chem’s Chemomics platform, we translated this dataset into actionable chemical matter from three avenues: (1) off-DNA resynthesis of enriched library compounds that are prioritized by our DEL-to-pharmacophore (Del2Ph4) analysis workflow and medicinal chemistry expertise, (2) compounds in commercial catalogs that score highly in DEL data-derived Machine Learning (ML) models and Del2Ph4 analysis, and (3) rapid parallel synthesis of analogs of enriched library compounds. SPR assays, both in-house at X-Chem and independently run by the Chordoma Foundation, have confirmed TBXT-binding activity for several distinct compounds, including the first noncovalent submicromolar TBXT ligand. These results highlight the power of X-Chem’s drug discovery platform and offer a path forward for Brachyury-targeted chordoma therapeutics.