Photo: Some of the CF Labs scientists behind our TBXT Challenge
We’re thrilled to share that the drug discovery service provider X-Chem has achieved a key milestone in the quest to develop drugs that target chordoma’s key vulnerability, brachyury, also known as TBXT.
Through participation in our ongoing drug discovery competition, the TBXT Challenge, they discovered a compound that binds to brachyury with far higher affinity than any previously published, surpassing the first of two critical thresholds that the Challenge seeks to reward.
For clearing this hurdle, X-Chem has earned the first of up to three prizes we are offering through our Challenge.
The challenge: drug the undruggable
Brachyury plays a crucial role in nearly every chordoma tumor but is largely absent from healthy tissues. This makes it a particularly promising treatment target for chordoma. It’s also thought to play a role in more common tumor types, including certain breast, colon, lung, and prostate cancers.
However, brachyury belongs to a category of proteins called transcription factors that have long been considered “undruggable” because they lack obvious places for a drug to attach. Of the hundreds of transcription factors implicated in human disease, only a handful have compounds that bind well enough to enable drug development.
Scientists have been working to overcome this obstacle to brachyury drug discovery for years. In 2017, a team collaborating through the Structural Genomics Consortium (SGC) mapped brachyury’s molecular structure, revealing places a drug might attach. By 2020, SGC researchers we funded along with the Mark Foundation for Cancer Research found the first compounds capable of binding to brachyury; later, the SGC team and others created improved compounds, but better binding was still needed for drugs to be developed.
Meanwhile, a proliferation of new technologies and tools began to offer a growing number of potential ways past this hurdle: like AI to help design or predict more potent binders, and new methods for creating and searching vast collections of chemical compounds.
To spur the application of these emerging approaches to brachyury, we launched the TBXT Challenge last year. Through the Challenge, competitors submit compounds to CF Labs, where our scientists measure their ability to bind to brachyury. The Challenge offers teams $100,000 for compounds that meet a first binding threshold (binding affinity below 1 micromolar), and $250,000 for those that meet an even lower, more demanding one (300 nanomolar).
Encouragingly, teams from 22 companies and four academic groups across nine countries have entered, bringing a wide range of expertise and approaches to this problem.
How X-Chem broke a barrier
To take on the TBXT Challenge, X-Chem screened its collection of more than 150 billion compounds (known as a DNA-encoded library, or DEL). Each compound carries a unique DNA tag that acts like a barcode. These tags let researchers screen many compounds at once, find the subset that appears to bind to the target, then read the tags to identify which compounds they’ve found. Using this approach, X-Chem found roughly 73,000 compounds that showed a signal of possible binding and warranted a closer look. From those, they used a combination of medicinal chemistry expertise, computational analysis, and machine learning to prioritize 76 for testing through the Challenge.
Our scientists in CF Labs then measured how well each of those compounds bound to brachyury using a technique called surface plasmon resonance, identifying one that appeared to meet the Challenge’s winning threshold.
Last week, X-Chem shared results from this work in a poster at the International DEL Symposium in Zurich. In parallel, we conducted multiple repeat tests of this compound in CF Labs and confirmed that it binds to brachyury at concentrations below the 1 micromolar Challenge threshold. That compound also passed an independent expert chemistry review which verified that its chemical structure meets Challenge criteria regarding suitability for further drug development, making X-Chem the first winner of our $100,000 prize.
The X-Chem team will present their work in a poster at our International Chordoma Research Workshop.
What this means for patients, and what comes next
X-Chem’s discovery is the first evidence that a compound can overcome a key and longstanding barrier that has held back brachyury drug discovery. This provides encouraging proof of principle that brachyury—and potentially other difficult-to-target transcription factors that contribute to various diseases—may be more “druggable” than previously assumed.
This is a promising starting point, but further work is needed to develop the compound into a drug. Regardless of the path forward for this particular compound, having crossed the first key threshold the Challenge sought to break, it provides an important precedent that we hope will be followed, including by other teams competing in the TBXT Challenge (prizes remain available for up to two more teams).
Crucially, such compounds—whether X-Chem’s winning compound, related compounds, or others yet to be discovered through the Challenge—could open the door to developing several types of promising drugs that have until now been out of reach for brachyury, such as PROTAC degraders, which are designed to direct a cell's own waste-disposal system to destroy a specific protein like brachyury.
As such, this discovery is an important step towards our objective to advance the first brachyury drugs into clinical trials by 2030, described in our Strategic Plan.
We’re deeply grateful to X-Chem and to all of the teams participating in the TBXT Challenge. We also appreciate all of our donors who made the Challenge possible, including the Mark Foundation for Cancer Research, Biohub, and others who helped us build the underlying capabilities in CF Labs.
We look forward to continuing the Challenge and hope that additional molecules will be identified that qualify for prizes. Meanwhile, you can accelerate our efforts to advance brachyury drug discovery by making a gift here or contacting our Head of Philanthropy, Kenny Brighton: kenny@chordoma.org.