Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays. Issue 9 (1st May 2017)

• Record Type: Journal Article
• Authors: Sun, Zhongya; Zhang, Hao; Chen, Zhifeng; Xie, Yiqian; Jiang, Hao; Chen, Limin; Ding, Hong; Zhang, Yuanyuan; Jiang, Hualiang; Zheng, Mingyue; Luo, Cheng
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 9(2017)
• Page Start: 2003
• Page End: 2009
• Publication Date: 2017-05-01
• Subjects: BRD4 inhibitor -- High-throughput screening -- Crystallography; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.03.012
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 ± 0.03 μM. 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 1.72 Å 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.