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Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype
- Publication Year :
- 2020
-
Abstract
- The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.
- Subjects :
- Male
BRD4
medicine.drug_class
Anti-Inflammatory Agents
Cell Cycle Proteins
Molecular Dynamics Simulation
Quinolones
01 natural sciences
Anti-inflammatory
BET inhibitor
03 medical and health sciences
Mice
Protein Domains
Cell Line, Tumor
Drug Discovery
medicine
Animals
Humans
QD
Epigenetics
Phylogeny
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
Small molecule
Phenotype
0104 chemical sciences
Amino acid
Bromodomain
Cell biology
010404 medicinal & biomolecular chemistry
chemistry
Drug Design
Leukocytes, Mononuclear
Molecular Medicine
Cytokines
Half-Life
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 00222623
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....a2071ff9f599969eeda5e1e32f456446