Creating open-source brachyury drugs
The key driver of chordoma, and its most promising drug target, is a protein called brachyury. Unfortunately, brachyury belongs to a class of proteins called transcription factors, which have historically been considered very difficult drug targets and thus are often called “undruggable.” Transcription factors are tricky from a drug development perspective because they typically lack active sites into which a traditional drug could fit and disrupt function. Thankfully, a team of world-renowned researchers at three institutions is making rapid progress toward overcoming these old barriers — and putting drugs against brachyury within reach.
In a pilot project started in 2018, Dr. David Drewry at the University of North Carolina, Dr. Opher Gileadi at the University of Oxford, and Dr. Charles Lin at Baylor College of Medicine succeeded in identifying a number of chemical fragments capable of binding to brachyury. Using one of the world’s most powerful X-ray machines, they discovered eight spots where small molecules could at least get a toehold. Each represents a possible point of attack against which a drug could be developed.
Using these brachyury-binding molecules as starting points, Dr. Paul Workman at the Institute of Cancer Research in London joined Drs. Drewry and Gileadi in 2019 in an attempt to create larger, more potent compounds with the properties needed to eventually create an effective drug against brachyury. With funding from The Chordoma Foundation and The Mark Foundation for Cancer Research, the team is now pursuing an audacious goal: develop compounds by the end of 2021 that can shut down brachyury in cells and provide templates for drugs that could be brought into clinical trials within two or three years thereafter.
Though no easy task, attacking difficult targets is not new to this team. Lead investigator Dr. Drewry has more than two decades of experience leading teams of chemists developing drugs against a variety of novel targets. Dr. Workman is widely known as one of the world’s most prolific drug hunters, having overseen teams both in industry and academia that cumulatively brought more than a dozen new cancer drugs into clinical trials. And Dr. Gileadi has made a career of tackling understudied proteins, including being the first to visualize the structure of human brachyury.
An exciting aspect of this endeavor is that it will follow the open-source playbook of the Structural Genomics Consortium (SGC), which means the project will be carried out in the open for other scientists to observe, contribute to, and build upon. There will be no secrets. No patents will be filed. And the chemical structures and associated data will be deposited into public databases in nearly real time. Because other researchers will be able to contribute ideas and new compounds to the project, this open-source approach has the potential to speed up the difficult work of brachyury drug discovery.
Most importantly, resulting compounds with therapeutic potential will not be licensed to just one company, as would typically be the case for patent-protected molecules. Instead, they will be available for anyone to further optimize into drug candidates suitable for human trials. In this way, the riskiest part of the drug discovery pathway can be done collaboratively, while leaving the door open for multiple independent parties to pursue later stages of therapeutic development.
Finally, because brachyury drives metastasis and resistance to therapy in many common cancers beyond chordoma, this endeavor — and the open-source precedent it sets — could inform the discovery of drugs to help hundreds of thousands of other cancer patients.
Why this project matters
The collaborators have already succeeded in the demanding task of identifying chemical fragments that can bind to brachyury. In doing so, they overcame a key hurdle that was not long ago thought to be insurmountable for so-called “undruggable” targets like brachyury. Building on this groundbreaking discovery, they are now on the cusp of developing new therapeutic compounds against brachyury. Such a drug could have a profound impact on the treatment of chordoma, which is dependent on brachyury for survival. It could also help prevent metastasis or treatment resistance of more common cancers, including breast, lung, and colon cancer. And because of its open-source approach, the larger scientific community can immediately contribute ideas and resources to this challenging project, which will accelerate the timeline for drug discovery.
Funding and support
- $150,000 Phase 1 Therapeutic Innovation Award from The Chordoma Foundation and The Mark Foundation for Cancer Research | 10/2018 – 10/2019
- $1,438,875 Phase 2 Therapeutic Innovation Award from The Chordoma Foundation and The Mark Foundation for Cancer Research | 12/2019 – 12/2021
- Contract medicinal chemistry and in-vivo drug screening services (>$700K)
- Access to chordoma cell lines
Brachyury Drug Discovery