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Updated: Mar 5, 2026
Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays
Zhongya Sun1, Hao Zhang2, Zhifeng Chen3
1School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China.
Abstract:
As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC50 value of 0.81±0.03μM. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72Å resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases.
Insights
Researchers discovered DCBD-005, a novel inhibitor targeting the BRD4-BD1 protein, crucial for cancer cell survival. This compound shows promise for developing new cancer therapies by blocking key interactions.
Area of Science:
- Epigenetics and molecular biology
- Cancer research and drug discovery
Background:
- BRD4 (Bromodomain-containing protein 4) acts as an epigenetic reader, controlling gene transcription vital for tumor cell survival.
- Targeting the first bromodomain of BRD4 (BRD4-BD1) with small molecules offers potential therapeutic strategies for BRD4-related cancers.
Purpose of the Study:
- To identify and characterize novel small molecular inhibitors of BRD4-BD1.
- To evaluate the anti-cancer effects of a newly identified inhibitor, DCBD-005, in leukemia cells.
- To elucidate the binding mechanism of DCBD-005 with BRD4-BD1 through structural analysis.
Main Methods:
- High-throughput screening using an AlphaScreen assay to identify BRD4-BD1 inhibitors.
- In vitro assays to assess the compound's effect on cell viability, cell cycle, and apoptosis in MV4-11 leukemia cells.
- X-ray crystallography to determine the co-crystal structure of DCBD-005 with BRD4-BD1.
Main Results:
- A novel inhibitor, DCBD-005, was identified with an IC50 of 0.81±0.03μM against BRD4-BD1.
- DCBD-005 demonstrated significant inhibition of leukemia cell viability, induced cell cycle arrest, and promoted apoptosis.
- The crystal structure revealed the binding mode of DCBD-005 to BRD4-BD1, providing insights for optimization.
Conclusions:
- DCBD-005 is a potent BRD4-BD1 inhibitor with demonstrated anti-leukemic activity.
- The structural insights facilitate structure-based drug design for improved BRD4-BD1 inhibitors.
- DCBD-005 represents a promising drug candidate for treating BRD4-related cancers.
