Abstract 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 500 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 exact DEL-encoded structures (library compounds) that are prioritized by our DEL-to-pharmacophore (Del2Ph4) analysis workflow, (2) compounds in commercial catalogs that score highly in Machine Learning (ML) models built from the DEL data and Del2Ph4 analysis, and (3) rapid parallel synthesis of analogs of enriched library compounds using multicomponent reactions. SPR assays using full-length Brachyury protein, independently run by the Chordoma Foundation, have confirmed target-binding activity for several chemically distinct compounds. These results highlight the power of X-Chem’s drug discovery platform and offer a path forward for Brachyury-targeted chordoma therapeutics. Citation Format: Zhen Chen, Rebecca Swett, Miklos Feher, AJ Baghaie, Jeffrey Santandrea, Philippe McGee, Massaba Keita, Jenny Liu, Ying Zhang, Jithender Vakiti, Natalia Sannikova, Julien Pomarole, Timothy Morgan, Jean-Christophe Grenier-Petel, Aurélien Coelho, Ryan Walsh, Dylan Hale, Faraz Hussain, Arnaud Clerc. DEL data-driven discovery of Brachyury (TBXT) ligands toward chordoma therapeutics abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4771.
Chen et al. (Fri,) studied this question.