期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 9, 页码 2003-2009出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.03.012
关键词
BRD4 inhibitor; High-throughput screening; Crystallography
资金
- Computer Network Information Center, Chinese Academy of Sciences
- Guangdong Supercomputing Center [2015-446]
- Ministry of Science and Technology of China [2015CB910304]
- National Natural Science Foundation of China [21472208, 91229205, 81625022, 21210003, 81230076, 81430084]
- Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science [TMC201505]
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 mu M. 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 angstrom 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. (C) 2017 Published by Elsevier Ltd.
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