Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy
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 transcri...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56213-1 |
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| author | Joseph A. Newman Angeline E. Gavard Nergis Imprachim Hazel Aitkenhead Hadley E. Sheppard Robert te Poele Paul A. Clarke Mohammad Anwar Hossain Louisa Temme Hans J. Oh Carrow I. Wells Zachary W. Davis-Gilbert Paul Workman Opher Gileadi David H. Drewry |
| author_facet | Joseph A. Newman Angeline E. Gavard Nergis Imprachim Hazel Aitkenhead Hadley E. Sheppard Robert te Poele Paul A. Clarke Mohammad Anwar Hossain Louisa Temme Hans J. Oh Carrow I. Wells Zachary W. Davis-Gilbert Paul Workman Opher Gileadi David H. Drewry |
| author_sort | Joseph A. Newman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a2c3997617084185b9fb4b7f8a653c7e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a2c3997617084185b9fb4b7f8a653c7e2025-08-20T02:43:11ZengNature PortfolioNature Communications2041-17232025-02-0116111410.1038/s41467-025-56213-1Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapyJoseph A. Newman0Angeline E. Gavard1Nergis Imprachim2Hazel Aitkenhead3Hadley E. Sheppard4Robert te Poele5Paul A. Clarke6Mohammad Anwar Hossain7Louisa Temme8Hans J. Oh9Carrow I. Wells10Zachary W. Davis-Gilbert11Paul Workman12Opher Gileadi13David H. Drewry14Centre for Medicines Discovery, University of OxfordCentre for Medicines Discovery, University of OxfordCentre for Medicines Discovery, University of OxfordCentre for Medicines Discovery, University of OxfordCentre for Cancer Drug Discovery, The Institute of Cancer ResearchCentre for Cancer Drug Discovery, The Institute of Cancer ResearchCentre for Cancer Drug Discovery, The Institute of Cancer ResearchSGC-UNC, University of North Carolina at Chapel HillSGC-UNC, University of North Carolina at Chapel HillSGC-UNC, University of North Carolina at Chapel HillSGC-UNC, University of North Carolina at Chapel HillSGC-UNC, University of North Carolina at Chapel HillCentre for Cancer Drug Discovery, The Institute of Cancer ResearchCentre for Medicines Discovery, University of OxfordSGC-UNC, University of North Carolina at Chapel HillAbstract 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.https://doi.org/10.1038/s41467-025-56213-1 |
| spellingShingle | Joseph A. Newman Angeline E. Gavard Nergis Imprachim Hazel Aitkenhead Hadley E. Sheppard Robert te Poele Paul A. Clarke Mohammad Anwar Hossain Louisa Temme Hans J. Oh Carrow I. Wells Zachary W. Davis-Gilbert Paul Workman Opher Gileadi David H. Drewry Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy Nature Communications |
| title | Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy |
| title_full | Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy |
| title_fullStr | Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy |
| title_full_unstemmed | Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy |
| title_short | Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy |
| title_sort | structural insights into human brachyury dna recognition and discovery of progressible binders for cancer therapy |
| url | https://doi.org/10.1038/s41467-025-56213-1 |
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