Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain
The transcriptional co-regulator ATAD2 is a prognostic marker for patient survival in many cancers. ATAD2 harbours a bromodomain which may offer an opportunity for pharmacological intervention, but its shallow, polar binding surface makes the development of inhibitors challenging. Here we optimized...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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Royal Society of Chemistry
2014
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| _version_ | 1797084964869636096 |
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| author | Chaikuad, A Petros, A Fedorov, O Xu, J Knapp, S |
| author_facet | Chaikuad, A Petros, A Fedorov, O Xu, J Knapp, S |
| author_sort | Chaikuad, A |
| collection | OXFORD |
| description | The transcriptional co-regulator ATAD2 is a prognostic marker for patient survival in many cancers. ATAD2 harbours a bromodomain which may offer an opportunity for pharmacological intervention, but its shallow, polar binding surface makes the development of inhibitors challenging. Here we optimized crystal transfer/soaking conditions enabling crystallographic fragment screening. We describe nine crystal structures of fragments including thymidine, a novel acetyl-lysine mimetic ligand and the evaluation of the binding properties of the identified fragments using NMR chemical shift perturbation experiments. The presented binding modes offer chemical starting points for the development of more potent ATAD2 inhibitors. This journal is |
| first_indexed | 2024-03-07T02:02:29Z |
| format | Journal article |
| id | oxford-uuid:9dd41f9b-0290-446d-a506-1595a4210bb7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:02:29Z |
| publishDate | 2014 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:9dd41f9b-0290-446d-a506-1595a4210bb72022-03-27T00:45:57ZStructure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomainJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9dd41f9b-0290-446d-a506-1595a4210bb7EnglishSymplectic Elements at OxfordRoyal Society of Chemistry2014Chaikuad, APetros, AFedorov, OXu, JKnapp, SThe transcriptional co-regulator ATAD2 is a prognostic marker for patient survival in many cancers. ATAD2 harbours a bromodomain which may offer an opportunity for pharmacological intervention, but its shallow, polar binding surface makes the development of inhibitors challenging. Here we optimized crystal transfer/soaking conditions enabling crystallographic fragment screening. We describe nine crystal structures of fragments including thymidine, a novel acetyl-lysine mimetic ligand and the evaluation of the binding properties of the identified fragments using NMR chemical shift perturbation experiments. The presented binding modes offer chemical starting points for the development of more potent ATAD2 inhibitors. This journal is |
| spellingShingle | Chaikuad, A Petros, A Fedorov, O Xu, J Knapp, S Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain |
| title | Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain |
| title_full | Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain |
| title_fullStr | Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain |
| title_full_unstemmed | Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain |
| title_short | Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain |
| title_sort | structure based approaches towards identification of fragments for the low druggability atad2 bromodomain |
| work_keys_str_mv | AT chaikuada structurebasedapproachestowardsidentificationoffragmentsforthelowdruggabilityatad2bromodomain AT petrosa structurebasedapproachestowardsidentificationoffragmentsforthelowdruggabilityatad2bromodomain AT fedorovo structurebasedapproachestowardsidentificationoffragmentsforthelowdruggabilityatad2bromodomain AT xuj structurebasedapproachestowardsidentificationoffragmentsforthelowdruggabilityatad2bromodomain AT knapps structurebasedapproachestowardsidentificationoffragmentsforthelowdruggabilityatad2bromodomain |