title: Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization.
abstract: The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 μM in FP binding assay and GI50 of 0.1-0.3 μM in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, ‡Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, and §Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Zhao
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Danyan
authors.initials: D
authors.lastname: Cao
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Li
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Danqi
authors.initials: D
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Yue-Lei
authors.initials: YL
authors.lastname: Chen
authors.forename: Guangxin
authors.initials: G
authors.lastname: Xia
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.forename: Yijyun
authors.initials: Y
authors.lastname: Lin
authors.forename: Zehong
authors.initials: Z
authors.lastname: Miao
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D053778:Thiazolidines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins