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Identification and development of 2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-one inhibitors targeting bromodomains within the switch/sucrose nonfermenting complex

Abstract:
Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.
Publication status:
Published
Peer review status:
Peer reviewed
Version:
Publisher's version

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Publisher copy:
10.1021/acs.jmedchem.5b01997

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Institution:
University of Oxford
Division:
Medical Sciences Division
Department:
NDM; Structural Genomics Consortium
Role:
Author
More by this author
Institution:
University of Oxford
Division:
Medical Sciences Division
Department:
NDM; Structural Genomics Consortium
Role:
Author
More by this author
Institution:
University of Oxford
Division:
Medical Sciences Division
Department:
NDM; Structural Genomics Consortium
Role:
Author
Expand authors...
Publisher:
American Chemical Society Publisher's website
Journal:
Journal of medicinal chemistry Journal website
Volume:
59
Issue:
10
Pages:
5095-5101
Publication date:
2016-04-27
DOI:
EISSN:
1520-4804
ISSN:
0022-2623
Pubs id:
pubs:619949
URN:
uri:6a445819-669d-404b-aee8-804e03dfdff1
UUID:
uuid:6a445819-669d-404b-aee8-804e03dfdff1
Local pid:
pubs:619949
Paper number:
10

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