title: Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors.
abstract: The bromodomain protein module and histone deacetylase (HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in cancer treatments. Herein we presented a novel design approach for cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The representative dual bromodomain/HDAC inhibitors, compound 11 and 12, showed potent antiproliferative activities against human leukaemia cell line K562 and MV4-11 in cellular assays. This work may lay the foundation for developing dual bromodomain/HDAC inhibitors as potential anticancer therapeutics.
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Hou
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ran
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Yanle
authors.initials: Y
authors.lastname: Zhi
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Tang
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: lutao@cpu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: ydchen@cpu.edu.cn.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
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; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007555:Isoxazoles; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Antiproliferative activity; Bromodomain; Epigenetic; HDAC; Protein–protein interactions