Dr. David Drewry. Photo by Jeyhoun Allebaugh/UNC-Chapel Hill Discovering drugs that strike at brachyury, the Achilles’ heel of chordoma, likely represents the most promising path to highly effective treatments for this disease — and possibly could aid in the treatment...
Brachyury Drug Discovery Initiative
Creating drugs that strike at the Achilles’ heel of chordoma
A large body of research points to brachyury as the key driver of chordoma, its most critical vulnerability, and its most promising drug target. Moreover, because brachyury is not present in normal human tissue, therapies targeting brachyury could, in principle, control chordoma without causing harm to patients. Yet, brachyury belongs to a class of proteins called transcription factors which have historically been considered difficult drug targets — often described as “undruggable.” Thankfully, a confluence of emerging technologies have the potential to overcome the barriers to drugging this important class of targets, and to put drugs against brachyury within reach. The goal of our Brachyury Drug Discovery Initiative is to bring every plausible technology to bear to make brachyury targeting therapies available to patients with chordoma and other cancers as quickly as possible. You can help us bring this unprecedented opportunity to fruition.
Brachyury is a protein encoded by the TBXT gene — a gene that everyone has in every cell of their body. The brachyury protein is vitally important during embryonic development, and is normally switched off after birth. However, it gets turned back on in a variety of tumors including chordoma. In certain tumors such as breast, lung, colon, and prostate cancers, it contributes to metastasis, resistance to therapy, and poor outcomes. In chordomas, brachyury doesn’t only contribute to bad behavior; it is the key driver of the disease. Laboratory research has shown that shutting off brachyury in chordoma cells renders them incapable of proliferating and prone to death.
In partnership with the Mark Foundation for Cancer Research, we are working to bring about the first therapies targeting brachyury by strategically initiating and investing in a portfolio of drug discovery projects pursuing a variety of therapeutic modalities. Initially, we are prioritizing development of targeted protein degraders and small molecule inhibitors, and at the same time exploring the feasibility of additional modalities such as RNA targeted small molecules, antisense oligonucleotides, DARPins, and others.
In parallel, we are investing in research to develop critical understanding of brachyury’s function, and to develop essential R&D enabling resources, including the tools needed to identify new drug candidates and test their effects on brachyury.
We are proud to partner with the Mark Foundation for Cancer Research to invest in research applying innovative approaches and technologies to brachyury drug discovery, which could serve as proof of concept for drugging other difficult targets.
|Virtual chemical screen to identify brachyury binders||Anders Näär, PhD – UC Berkeley||Ongoing|
|Phenotypic screen for inhibitors of brachyury function||Slim Sassi, PhD – Massachusetts General Hospital||Ongoing|
|Chemoproteomic based drug discovery||Dan Nomura, PhD – UC Berkeley||Ongoing|
|Abolishing brachyury function through degradation||Craig Crews, PhD – Yale||Ongoing|
|Structure-guided drug discovery for brachyury inhibitors||David Drewry, PhD – UNC
Opher Gileadi, PhD – Oxford
Paul Workman, PhD – ICR
|Identifying and targeting brachyury transcriptional deregulation in chordoma||Charles Lin, PhD – Baylor College of Medicine||Complete|
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