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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

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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
More from this funder
Name:
Engineering and Physical Sciences Research Council
Funding agency for:
Ley, S
Grant:
EP/K039520/1
More from this funder
Name:
Cambridge Ph.D. Training Programme in Chemical Biology and Molecular Medicine
Funding agency for:
Sutherell, C
Publisher:
American Chemical Society
Journal:
Journal of medicinal chemistry More from this journal
Volume:
59
Issue:
10
Pages:
5095-5101
Publication date:
2016-04-27
DOI:
EISSN:
1520-4804
ISSN:
0022-2623
Pmid:
27119626
Language:
English
Keywords:
Pubs id:
pubs:619949
UUID:
uuid:6a445819-669d-404b-aee8-804e03dfdff1
Local pid:
pubs:619949
Source identifiers:
619949
Deposit date:
2017-12-20

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