There are currently no systemic therapies approved to treat chordoma, a rare bone cancer of the spine or base of the skull responsible for substantial morbidity and mortality of patients. The transcription factor brachyury is thought to drive chordoma pathogenesis, as well as contribute to metastatic potential in many other types of cancer. Because brachyury is minimally expressed in healthy adult tissue, the development of selective brachyury inhibitors is a promising targeted therapeutic strategy for chordoma. The Mark Foundation, in partnership with the Chordoma Foundation, is supporting a collaborative effort with the Drewry, Gileadi, and Workman labs to use structure-guided, fragment-based drug design to identify and characterize compounds that directly bind brachyury. This project is an expansion of a successful pilot study funded by both foundations in which Drewry and Gileadi (together with Charles Lin at Baylor College of Medicine) mapped out several potentially druggable sites on brachyury using X-ray crystallography, including sites for ligands that bind both reversibly and non-reversibly. They are now using this 3-dimensional structural information to inform the design of drug-like molecules that can bind brachyury. Promising small-molecule tool compounds will be advanced into cellular assays to determine the effects of brachyury modulation in chordoma. The researchers are pursuing an open-science approach, providing the larger scientific community with immediate access to both experimental results and the chemical and biological reagents developed throughout the study. The ultimate goal of the project is the identification of one or more selective compounds that can be developed into a drug to treat chordoma.
Sheppard HE, Dall’Agnese A, Park WD, Shamim MH, Dubrulle J, Johnson HL, Stossi F, Cogswell P, Sommer J, Levy J, Sharifnia T, Wawer MJ, Nabet B, Gray NS, Clemons PA, Schreiber SL, Workman P, Young RA, Lin CY. Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity. Cell Reports Med. 2021.