title: Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation.
abstract: The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.|University of Chinese Academy of Sciences , No. 19 Yuquan Road, Beijing 100049, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Xue
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.|Department of Bioengineering School of Pharmaceutical Sciences, Jilin University , No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
authors.forename: Zhaoxuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Song
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.|Department of Bioengineering School of Pharmaceutical Sciences, Jilin University , No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.|University of Chinese Academy of Sciences , No. 19 Yuquan Road, Beijing 100049, China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Department of Bioengineering School of Pharmaceutical Sciences, Jilin University , No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
authors.forename: Yulai
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007211:Indoles; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins