A big leg up for brachyury drug discovery

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 of other cancers in which brachyury plays a role.

The linchpin, and what has been missing until now, are chemical compounds that can bind strongly and specifically to the brachyury protein, thus serving as a jumping off point for designing drugs that either disrupt brachyury’s function or trigger its destruction.

Now, in a leap forward, grantees through our Brachyury Drug Discovery Initiative have achieved something once thought to be improbable: they’ve developed numerous chemical compounds capable of binding robustly to brachyury.

Previously, with pilot funding from the Chordoma Foundation and The Mark Foundation for Cancer Research, scientists at the University of North Carolina, the University of Oxford, and the Institute of Cancer Research identified multiple spots on the brachyury protein where compounds could bind weakly, providing a toehold from which to create more potent binders.

Building on this initial breakthrough, two years ago, in partnership with The Mark Foundation and the Marcus Foundation, we invested in an industrial-scale effort to optimize these initial hits into compounds capable of actually eliminating brachyury in cells.

Since then, the investigators have designed and produced around 3,500 new compounds — a massive number by academic standards — and tested them for their ability to bind to brachyury. Remarkably, a number of these new compounds bind to brachyury 100 times more potently than any compounds known at the beginning of their project.

This extraordinary progress goes a long way towards removing one of the biggest sources of uncertainty and risk in the quest to develop drugs against brachyury: there is now little reason to believe that brachyury is “undruggable,” as it was assumed to be until recently.

From here, the aim is to further enhance these compounds to a critical inflection point where they can reliably eliminate brachyury in cells and animal models — in drug development parlance, compounds at that point are known as “probes.” Once available, these probes will serve as advanced templates from which to design drugs for eventual clinical trials, and to enable researchers to study and validate brachyury as a target in other types of cancer, including breast, lung, colon, and prostate.

Ordinarily, data behind progress like this would be carefully guarded with the intent of maintaining a large advantage over potential competitors. But this project follows the open-source playbook of the Structural Genomics Consortium, so all of the chemical structures have already been publicly shared. As a result, any researcher or company venturing into brachyury drug discovery will have a big head start, and can avoid the time, risk of failure, and duplicative expense of repeating this phase of the project themselves. By bridging the “valley of death” in drug development — the risky gap between early discovery and when market incentives can drive further investments — this project is making the challenging work of brachyury drug discovery much more feasible for other teams. And, as our grantees continue their work towards developing brachyury probes, additional data will be released for anyone to build on at any time.

This project is not only serving to de-risk brachyury drug discovery, but also setting a precedent for drugging other difficult targets in the future. We’re grateful to The Mark Foundation for Cancer Research, the Marcus Foundation, and everyone who has contributed to this project for boldly helping us tackle a problem most others assumed was impossible. Because of the catalytic investments we’ve made together, the path to bringing brachyury drugs to patients is becoming much clearer. With continued effort, we’re excited to see this project race across the finish line, and the subsequent investments the resulting probes will attract.