title: Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors.
abstract: BRD4 plays a key role in transcriptional regulation. Recent biological and pharmacological studies have demonstrated that bromodomain-containing protein 4 (BRD4) is a viable drug target for cancer treatment. In this study, we synthesized a series of dihydroquinoxalinone derivatives and evaluated their BRD4 inhibitory activities, obtaining compound 5i with IC50 value of 73nM of binding activity in BRD4(1) and 258nM of cellular activity in MV-4-11 cancer cell lines. Docking studies were performed to explain the structure-activity relationship. Based on its potent biochemical and anti-proliferative activity, the novel BRD4 inhibitor compound 5i, is a promising lead compound for further investigation.
authors: Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors: Yifei
authors: Y
authors: Yang
authors: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors: Leilei
authors: L
authors: Zhao
authors: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors: Bin
authors: B
authors: Xu
authors: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors: LingYun
authors: L
authors: Yang
authors: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors: Jian
authors: J
authors: Zhang
authors: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors: Huibin
authors: H
authors: Zhang
authors: Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.
authors: Jinpei
authors: J
authors: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011810:Quinoxalines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000620880:dihydroquinoxalinone
keywords: BRD4 inhibitors; Cancer; Dihydroquinoxalinone derivatives; Molecular docking