Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery
Abstract Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recogn...
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2021
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oai:doaj.org-article:5972f93c7d5b4a20bcf0f3bca48972272021-12-02T14:12:41ZDiscovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery10.1038/s41598-020-80588-42045-2322https://doaj.org/article/5972f93c7d5b4a20bcf0f3bca48972272021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80588-4https://doaj.org/toc/2045-2322Abstract Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recognizes the heterochromatin-associated histone mark H3K9me3 and supports intramolecular contacts with other regions of UHRF1. Using both binding-based and function-based screens of a ~ 2300-fragment library in parallel, we identified 2,4-lutidine as a hit for follow-up NMR and X-ray crystallography studies. Unlike previous reported ligands, 2,4-lutidine binds to two binding pockets that are in close proximity on TTD and so has the potential to be evolved into more potent inhibitors using a fragment-linking strategy. Our study provides a useful starting point for developing potent chemical probes against UHRF1.Lyra ChangJames CampbellIdris O. RajiShiva K. R. GuduruPrasanna KandelMichelle NguyenSteven LiuKevin TranNavneet K. VenugopalBethany C. TaylorMatthew V. HoltNicolas L. YoungErrol L. G. SamuelPrashi JainConrad SantiniBanumathi SankaranKevin R. MacKenzieDamian W. YoungNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021) |
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Medicine R Science Q Lyra Chang James Campbell Idris O. Raji Shiva K. R. Guduru Prasanna Kandel Michelle Nguyen Steven Liu Kevin Tran Navneet K. Venugopal Bethany C. Taylor Matthew V. Holt Nicolas L. Young Errol L. G. Samuel Prashi Jain Conrad Santini Banumathi Sankaran Kevin R. MacKenzie Damian W. Young Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery |
| description |
Abstract Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recognizes the heterochromatin-associated histone mark H3K9me3 and supports intramolecular contacts with other regions of UHRF1. Using both binding-based and function-based screens of a ~ 2300-fragment library in parallel, we identified 2,4-lutidine as a hit for follow-up NMR and X-ray crystallography studies. Unlike previous reported ligands, 2,4-lutidine binds to two binding pockets that are in close proximity on TTD and so has the potential to be evolved into more potent inhibitors using a fragment-linking strategy. Our study provides a useful starting point for developing potent chemical probes against UHRF1. |
| format |
article |
| author |
Lyra Chang James Campbell Idris O. Raji Shiva K. R. Guduru Prasanna Kandel Michelle Nguyen Steven Liu Kevin Tran Navneet K. Venugopal Bethany C. Taylor Matthew V. Holt Nicolas L. Young Errol L. G. Samuel Prashi Jain Conrad Santini Banumathi Sankaran Kevin R. MacKenzie Damian W. Young |
| author_facet |
Lyra Chang James Campbell Idris O. Raji Shiva K. R. Guduru Prasanna Kandel Michelle Nguyen Steven Liu Kevin Tran Navneet K. Venugopal Bethany C. Taylor Matthew V. Holt Nicolas L. Young Errol L. G. Samuel Prashi Jain Conrad Santini Banumathi Sankaran Kevin R. MacKenzie Damian W. Young |
| author_sort |
Lyra Chang |
| title |
Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery |
| title_short |
Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery |
| title_full |
Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery |
| title_fullStr |
Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery |
| title_full_unstemmed |
Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery |
| title_sort |
discovery of small molecules targeting the tandem tudor domain of the epigenetic factor uhrf1 using fragment-based ligand discovery |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/5972f93c7d5b4a20bcf0f3bca4897227 |
| work_keys_str_mv |
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