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Announcing three new investments to catalyze brachyury drug discovery

Each of these projects will start by employing a different approach to identify chemical compounds that can bind to brachyury.

Brachyury drug discovery grants

We are pleased to announce that the Chordoma Foundation and The Mark Foundation for Cancer Research (MFCR) have together awarded three new grants to support innovative research projects aimed at discovering the first drugs that target brachyury – a protein believed to be the Achilles’ heel of chordoma and a driver of metastasis in many other cancers.

Brachyury belongs to a class of proteins called transcription factors, which have historically been considered “undruggable” due to the lack of features on their structure to which drugs can readily bind. But a host of new technologies and drug discovery strategies are challenging the concept of “undruggable,” providing, for the first time, a plausible path to creating therapies against many disease-linked transcription factors.

These new awards will enable investigators at the forefront of developing such approaches to use brachyury as an early test case. If successful, they will not only result in the first therapies that directly target brachyury, but also will serve as a proof of concept for developing drugs against other transcription factors, which are implicated in nearly all cancers and more than 250 other diseases.

About the awards

Earlier this year, the Chordoma Foundation and The Mark Foundation jointly launched the Therapeutic Innovation Award – a grants program designed to catalyze brachyury drug discovery research using innovative approaches and technologies. We were thrilled to receive a stellar pool of applicants, many from top-tier investigators who had not previously been involved in chordoma research. Based on a rigorous peer-review process, three high-impact projects were selected for our joint investment:

  1. PROteolysis TArgeting Chimeras (PROTACs) for the targeted degradation of brachyury
    Attempting to eliminate brachyury by harnessing the innate cellular system for destroying faulty proteins – a process called protein degradation.
    • Investigator: Craig Crews, PhD | Yale University
  1. Chemoproteomic platforms to develop a brachyury inhibitor
    Employing novel chemistry techniques to discover molecules that bind strongly and irreversibly to the brachyury protein, providing a foothold for constructing compounds that either directly inhibit brachyury’s function or PROTACs to trigger its degradation. This work will be performed in the context of a broader ASPIRE project funded by The Mark Foundation to target “undruggable” proteins implicated in cancer.
    • Investigator: Daniel Nomura, PhD | University of California, Berkeley
  1. A structure-guided drug discovery pipeline for direct brachyury inhibitors
    Developing a high-resolution map of the physical structure of the brachyury protein and constructing drugs based on identifying small chemical structures (“chemical fragments”) that interface with subtle features in the protein.
    • Investigators:
      Opher Gileadi, PhD | Oxford University
      David Drewry, PhD | University of North Carolina, Chapel Hill
      Charles Lin, PhD | Baylor College of Medicine

Each of these projects will start by employing a different approach to identify chemical compounds that can bind to brachyury. Discovering such a binder (called a “ligand”) will serve as a starting point for two downstream therapeutic development pathways: one to develop drugs that block the function of brachyury and one to develop drugs that cause brachyury to be degraded and ultimately eliminated.

Our investments in these projects are structured in two phases. The first phase is a one-year $150,000 pilot grant intended to assess feasibility and generate preliminary data. If successful, awardees will be eligible to apply for a second phase of funding, which will support a multi-year continuation of the project, with the goal of creating a path towards clinical development.

Made possible by the generosity of The Mark Foundation, the grants will be administered and overseen by the Chordoma Foundation. We will also provide in-kind support including access to disease models and preclinical evaluation of candidate compounds through our Drug Screening Program.

A coordinated, team approach

Beyond applying cutting-edge technologies to brachyury drug discovery, what’s particularly exciting to us about these awards is that they bring together a world-class team of researchers to work in concert towards a common goal. Each of the five investigators involved is a pioneer in their own domain and brings to the table highly complementary expertise and capabilities that have the potential to advance the others’ work.

To jump-start collaboration between the grantees, we convened a kick-off meeting with all five investigators earlier this month. From this meeting, a number of ideas emerged for collaboration, as well as a shared commitment to regular communication and data sharing.

Going forward, as members of the team identify additional data or materials that they need, the others stand ready to help meet the need. And if necessary, the Chordoma Foundation and The Mark Foundation are prepared to bring in outside expertise or resources to ensure that the projects proceed without delay.

“The Foundation’s active role in bringing together research groups with complementary capabilities will probably shorten the time to achieve our goals by at least 50 percent.”

Opher Gileadi, PhD, University of Oxford

Potential impact

Together, these projects represent a significant step towards the Chordoma Foundation’s chief research goal of developing therapies targeting brachyury. Such a drug could have a profound impact on the treatment of chordoma, which is dependent on brachyury for survival, and could potentially help prevent metastasis of more common cancers, including breast, lung and colon cancer.

In the process, these projects will produce data and tools that can benefit the work of other investigators studying brachyury in the context of chordoma and other diseases. Additionally, we anticipate that lessons from these projects could inform the development of drugs against the roughly 300 other cancer-associated transcription factors, nearly all of which currently remain undruggable.

Valued partnerships

The Chordoma Foundation deeply values the partnership we have forged with The Mark Foundation to advance our shared interests in discovering new drugs against brachyury and setting an example for other undruggable cancer targets. We are also grateful to the truly outstanding investigators and all of the personnel in their labs who, through these projects, are devoting their time and talents to solving a problem of great significance to all affected by chordoma. Finally, we wish to thank everyone whose investment in the Chordoma Foundation has enabled this research to come to fruition. We look forward to keeping you apprised as these projects move ahead and we welcome inquiries from anyone interested in learning more.

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