BIOMAT Database Logo BIOMAT Database Logo

Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors. 2020

Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.

Bromodomain protein 4 (BRD4) plays a crucial role in transcriptional regulation and is considered to be a viable drug target for cancer treatment. Herein, we designed and synthesized a series of indole-2-one derivatives through scaffold hopping drug design. Most of the compounds showed potent BRD4 inhibitory activities and anti-proliferation activities in cancer cell lines. Especially, compound 12j exhibited excellent BRD4 inhibitory activities (BD1 IC50 = 19 nM, BD2 IC50 = 28 nM) and anti-proliferation potency with IC50 values of 4.75 μM and 1.35 μM in HT-29 and HL-60 cells, respectively. Additionally, docking studies showed that the hydrophobic pocket next to KAc region and WPF shelf were critical to the activity of the compound. Compound 12j could arrest the cell-cycle progression of HT-29 cells into the G1 phase and reduce the expression of c-Myc. Moreover, compound 12j exhibited favorable oral pharmacokinetic properties. All the results demonstrated that compound 12j was a potent BRD4 inhibitor and had merely potential for colon cancer treatment.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular

Related Publications

Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling.
May 2007, Bioorganic & medicinal chemistry letters,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis and biological evaluation of indole derivatives as Vif inhibitors.
September 2017, Bioorganic & medicinal chemistry letters,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors.
November 2023, Bioorganic & medicinal chemistry letters,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Discovery of indole-2-one derivatives as BRD4 (BD1) selective inhibitors.
May 2024, Bioorganic & medicinal chemistry,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis and biological evaluation of novel indolin-2-one derivatives as potent second-generation TRKs inhibitors.
May 2023, European journal of medicinal chemistry,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents.
March 2019, Bioorganic chemistry,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis and biological evaluation of benzo[cd]indol-2(1H)-ones derivatives as BRD4 inhibitors.
May 2018, European journal of medicinal chemistry,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis, and biological evaluation of phenylurea indole derivatives as ABCG2 inhibitors.
June 2023, Bioorganic chemistry,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors.
October 2019, Bioorganic & medicinal chemistry letters,
Yu Xu, and Xiu-Juan Zhang, and Wen-Bo Li, and Xing-Rong Wang, and Shuai Wang, and Xue-Peng Qiao, and Shi-Wu Chen
Design, Synthesis, and in vitro Biological Evaluation of 3,5-Dimethylisoxazole Derivatives as BRD4 Inhibitors.
July 2018, ChemMedChem,
Copied contents to your clipboard!