PUBLICATION
Discovery of a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer
- Authors
- Ouyang, L., Zhang, L., Liu, J., Fu, L., Yao, D., Zhao, Y., Zhang, S., Wang, G., He, G., Liu, B.
- ID
- ZDB-PUB-171128-2
- Date
- 2017
- Source
- Journal of medicinal chemistry 60(24): 9990-10012 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- AMP-Activated Protein Kinases/metabolism*
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Autophagy/drug effects*
- Breast Neoplasms/drug therapy*
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Crystallography, X-Ray
- Drug Screening Assays, Antitumor
- Embryo, Nonmammalian/drug effects
- Female
- Humans
- Mice, Inbred BALB C
- Molecular Docking Simulation
- Nuclear Proteins/antagonists & inhibitors*
- Nuclear Proteins/chemistry
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Small Molecule Libraries/chemistry
- Small Molecule Libraries/pharmacology
- Structure-Activity Relationship
- Transcription Factors/antagonists & inhibitors*
- Transcription Factors/chemistry
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Xenograft Model Antitumor Assays
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 29172540 Full text @ J. Med. Chem.
Citation
Ouyang, L., Zhang, L., Liu, J., Fu, L., Yao, D., Zhao, Y., Zhang, S., Wang, G., He, G., Liu, B. (2017) Discovery of a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer. Journal of medicinal chemistry. 60(24):9990-10012.
Abstract
Based upon The Cancer Genome Atlas (TCGA) dataset, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) was remarkably downregulated in breast cancer. Combined with co-immunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4 8f (FL-411) which was validated by co-crystal structure with BD1 of BRD4. Subsequently, 8f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction, and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 8f induced ACD pathways, involved in HMGB1, VDAC1/2 and eEF2. Moreover, 8f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping