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BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability

Abstract:

Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t½ = 39.8 min). Str...

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Publication status:
Published
Peer review status:
Peer reviewed
Version:
Publisher's version

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Publisher copy:
10.1016/j.bmc.2018.05.003

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Institution:
University of Oxford
Division:
MPLS Division
Department:
Chemistry; Organic Chemistry
Role:
Author
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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:
MPLS Division
Department:
Chemistry; Organic Chemistry
Role:
Author
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GlaxoSmithKline More from this funder
German Research Foundation More from this funder
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Publisher:
Elsevier Publisher's website
Journal:
Bioorganic and Medicinal Chemistry Journal website
Volume:
26
Issue:
11
Pages:
2937-2957
Publication date:
2018-05-15
Acceptance date:
2018-05-02
DOI:
EISSN:
1464-3391
ISSN:
0968-0896
Pubs id:
pubs:852973
URN:
uri:8a90387b-56d0-4a89-89fd-ead0042e89c7
UUID:
uuid:8a90387b-56d0-4a89-89fd-ead0042e89c7
Local pid:
pubs:852973
Language:
English
Keywords:

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