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Updated: May 28, 2025
Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC Crosslinking of Small Molecules to Isolate Chromatin
Published on: January 20, 2016
Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy
Joseph A Newman1, Angeline E Gavard2,3, Nergis Imprachim2,4
1Centre for Medicines Discovery, University of Oxford, Oxford, UK. Joseph.newman@cmd.ox.ac.uk.
Abstract:
Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low µM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches.
Insights
Researchers found that the transcription factor brachyury, a target in chordoma and other cancers, can be targeted by small molecules. This study demonstrates brachyury is druggable, opening new therapeutic avenues for difficult-to-treat solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Structural Biology
Background:
- Brachyury is a transcription factor crucial for chordoma tumor growth and present in other solid tumors.
- Minimal expression in healthy tissues makes brachyury an attractive therapeutic target.
- Brachyury's nature as a ligandless transcription factor historically deemed it undruggable.
Purpose of the Study:
- To investigate the direct targeting of brachyury by small molecules.
- To understand brachyury's DNA binding mechanisms and the G177D variant in chordoma.
Main Methods:
- Determined the structure of human brachyury alone and bound to DNA.
- Employed crystallographic fragment screening to identify surface binding pockets.
- Conducted medicinal chemistry on fragment hits to develop potent binders.
Main Results:
- Structural insights into brachyury-DNA interactions and the G177D variant were obtained.
- Fragment screening identified multiple druggable pockets on the brachyury surface.
- A thiazole chemical series progressed to low micromolar potency binders.
Conclusions:
- Brachyury is demonstrated to be a ligandable target.
- Crystallographic fragment screening is effective for targeting historically undruggable proteins.
- This work provides a foundation for developing novel therapeutics against brachyury-driven cancers.
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