Cargando…
A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction**
The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent...
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
WILEY-VCH Verlag
2014
|
| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298791/ https://www.ncbi.nlm.nih.gov/pubmed/24821300 http://dx.doi.org/10.1002/anie.201402750 |
| _version_ | 1782353296649879552 |
|---|---|
| author | Rooney, Timothy P C Filippakopoulos, Panagis Fedorov, Oleg Picaud, Sarah Cortopassi, Wilian A Hay, Duncan A Martin, Sarah Tumber, Anthony Rogers, Catherine M Philpott, Martin Wang, Minghua Thompson, Amber L Heightman, Tom D Pryde, David C Cook, Andrew Paton, Robert S Müller, Susanne Knapp, Stefan Brennan, Paul E Conway, Stuart J |
| author_facet | Rooney, Timothy P C Filippakopoulos, Panagis Fedorov, Oleg Picaud, Sarah Cortopassi, Wilian A Hay, Duncan A Martin, Sarah Tumber, Anthony Rogers, Catherine M Philpott, Martin Wang, Minghua Thompson, Amber L Heightman, Tom D Pryde, David C Cook, Andrew Paton, Robert S Müller, Susanne Knapp, Stefan Brennan, Paul E Conway, Stuart J |
| author_sort | Rooney, Timothy P C |
| collection | PubMed |
| description | The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation–π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells. |
| format | Online Article Text |
| id | pubmed-4298791 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2014 |
| publisher | WILEY-VCH Verlag |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-42987912015-01-27 A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** Rooney, Timothy P C Filippakopoulos, Panagis Fedorov, Oleg Picaud, Sarah Cortopassi, Wilian A Hay, Duncan A Martin, Sarah Tumber, Anthony Rogers, Catherine M Philpott, Martin Wang, Minghua Thompson, Amber L Heightman, Tom D Pryde, David C Cook, Andrew Paton, Robert S Müller, Susanne Knapp, Stefan Brennan, Paul E Conway, Stuart J Angew Chem Int Ed Engl Communications The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation–π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells. WILEY-VCH Verlag 2014-06-10 2014-05-12 /pmc/articles/PMC4298791/ /pubmed/24821300 http://dx.doi.org/10.1002/anie.201402750 Text en © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| spellingShingle | Communications Rooney, Timothy P C Filippakopoulos, Panagis Fedorov, Oleg Picaud, Sarah Cortopassi, Wilian A Hay, Duncan A Martin, Sarah Tumber, Anthony Rogers, Catherine M Philpott, Martin Wang, Minghua Thompson, Amber L Heightman, Tom D Pryde, David C Cook, Andrew Paton, Robert S Müller, Susanne Knapp, Stefan Brennan, Paul E Conway, Stuart J A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** |
| title | A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** |
| title_full | A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** |
| title_fullStr | A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** |
| title_full_unstemmed | A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** |
| title_short | A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation–π Interaction** |
| title_sort | series of potent crebbp bromodomain ligands reveals an induced-fit pocket stabilized by a cation–π interaction** |
| topic | Communications |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298791/ https://www.ncbi.nlm.nih.gov/pubmed/24821300 http://dx.doi.org/10.1002/anie.201402750 |
| work_keys_str_mv | AT rooneytimothypc aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT filippakopoulospanagis aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT fedorovoleg aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT picaudsarah aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT cortopassiwiliana aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT hayduncana aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT martinsarah aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT tumberanthony aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT rogerscatherinem aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT philpottmartin aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT wangminghua aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT thompsonamberl aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT heightmantomd aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT prydedavidc aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT cookandrew aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT patonroberts aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT mullersusanne aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT knappstefan aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT brennanpaule aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT conwaystuartj aseriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT rooneytimothypc seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT filippakopoulospanagis seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT fedorovoleg seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT picaudsarah seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT cortopassiwiliana seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT hayduncana seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT martinsarah seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT tumberanthony seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT rogerscatherinem seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT philpottmartin seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT wangminghua seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT thompsonamberl seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT heightmantomd seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT prydedavidc seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT cookandrew seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT patonroberts seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT mullersusanne seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT knappstefan seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT brennanpaule seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction AT conwaystuartj seriesofpotentcrebbpbromodomainligandsrevealsaninducedfitpocketstabilizedbyacationpinteraction |