Development of 4,5-dihydro-benzodiazepinone derivatives as a new chemical series of BRD4 inhibitors.
Bromodomains (BRDs) are protein interaction modules that selectively recognize ε -N-lysine residues, serving as key epigenetic readers and play a key role in epigenetic regulation of gene transcription. Bromodomain-containing protein 4 (BRD4), a protein containing two BRDs termed BD1 and BD2, has emerged as an attractive candidate for the development of inhibitors targeting gene transcription in several types of cancers. In this study, we made structural modifications of previously reported BRD4 inhibitors, to develop new chemical scaffold 3,4-dihydroquinoxalin-2(1H)-one. Four series of compounds (compounds 7-10) were synthesized, and the BRD4-inhibitory activity and anti-proliferative effect of these compounds were evaluated. We found compound 10d has remarkable anti-proliferative activities toward leukemia cells and could induce apoptosis by mitochondrial pathways. Notably, the analysis of molecular docking suggested that hydrophobic interaction was essential for compound 10d to bind to BD1. In conclusion, these results demonstrate the potential of compound 10d to be utilized as a BRD4 inhibitor with apoptosis inducing effect in future leukemia therapy.
School of Medicine, Zhejiang University City College, Hangzhou 310015, Zhejiang, China.
Jie
J
Li
State Key Laboratory of Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Peiqi
P
Wang
School of Medicine, Zhejiang University City College, Hangzhou 310015, Zhejiang, China.
Bihui
B
Zhou
State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China.
Jianyou
J
Shi
State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China.
Jie
J
Liu
School of Medicine, Zhejiang University City College, Hangzhou 310015, Zhejiang, China.
Xiangrong
X
Li
School of Medicine, Zhejiang University City College, Hangzhou 310015, Zhejiang, China.
Limei
L
Fan
State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China. Electronic address: zhengyaxinxyz@163.com.
Yaxin
Y
Zheng
State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China. Electronic address: ouyangliang@scu.edu.cn.
Liang
L
Ouyang
D001570:Benzodiazepinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D001570:Benzodiazepinones; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
Apoptosis; BRD4; Bromodomain inhibitors; Dihydrobenzodiazepinone; Epigenetics