Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays

Zhongya Sun; Hao Zhang; Zhifeng Chen; Yiqian Xie; Hao Jiang; Limin Chen; Hong Ding; Yuanyuan Zhang; Hualiang Jiang; Mingyue Zheng; Cheng Luo

doi:10.1016/j.bmcl.2017.03.012

Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays

Bioorg Med Chem Lett. 2017 May 1;27(9):2003-2009. doi: 10.1016/j.bmcl.2017.03.012. Epub 2017 Mar 9.

Authors

Zhongya Sun¹, Hao Zhang², Zhifeng Chen³, Yiqian Xie⁴, Hao Jiang⁴, Limin Chen⁵, Hong Ding⁶, Yuanyuan Zhang⁴, Hualiang Jiang⁴, Mingyue Zheng⁴, Cheng Luo⁷

Affiliations

¹ School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China.
² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
³ School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁵ School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China. Electronic address: lmchen0516@126.com.
⁶ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: hding@simm.ac.cn.
⁷ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China. Electronic address: cluo@simm.ac.cn.

PMID: 28347667
DOI: 10.1016/j.bmcl.2017.03.012

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.

Keywords: BRD4 inhibitor; Crystallography; High-throughput screening.

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Cycle Proteins
Cell Line, Tumor
Cell Survival / drug effects
Crystallography, X-Ray
High-Throughput Screening Assays
Humans
Leukemia / drug therapy*
Leukemia / metabolism
Models, Molecular
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / chemistry
Nuclear Proteins / metabolism
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology*
Transcription Factors / antagonists & inhibitors*
Transcription Factors / chemistry
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Nuclear Proteins
Small Molecule Libraries
Transcription Factors