J Med Chem
State Key Laboratory of Biotherapy and Cancer Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Published: April 2022
Blocking the interactions between bromodomain and extraterminal (BET) proteins and acetylated lysines of histones by small molecules has important implications for the treatment of cancers and other diseases. Many pan-BET inhibitors have shown satisfactory results in clinical trials, but their potential for poor tolerability and toxicity persist. However, recently reported studies illustrate that some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have advantage over pan-inhibitors, including reduced toxicity concerns. Furthermore, some selective BET inhibitors have similar or even better therapeutic efficacy in inflammatory diseases or cancers. Therefore, the development of selective BET inhibitors has become a hot spot for medicinal chemists. Here, we summarize the known selective BET-BD1 and BET-BD2 inhibitors and review the methods for enhancing the selectivity and potency of these inhibitors based on their different modes of interactions with BET-BD1 or BET-BD2. Finally, we discuss prospective strategies that selectively target the bromodomains of BET proteins.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01835 | DOI Listing |
BMC Cancer
January 2025
Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan.
Background: This study aimed to analyze the functional role of Brd4 in colorectal cancer (CRC) organoids. Brd4 was identified as a CRC-related gene by our previous Sleeping Beauty mutagenesis transposon screening in mice. Brd4 is a transcriptional regulator that recognizes acetylated histones and is known to be involved in inflammatory responses.
View Article and Find Full Text PDFJ Med Chem
January 2025
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor , we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors.
View Article and Find Full Text PDFImmunol Rev
March 2025
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Since their first description in 2008, T-bet+ B cells have emerged as a clinically important B cell subset. Now commonly known as ABCs (Age-associated B Cells), they are uniquely characterized by their expression of the transcription factor T-bet. Indeed, this singular factor defines this B cell subset.
View Article and Find Full Text PDFFront Immunol
January 2025
Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Object: We aim to explore the immunomodulatory properties of T cells on different titanium nanotubes and the key immunological factors involved in this process.
Methods: Transcriptome data from GEO database of healthy people and healthy implants were used to analyze cell infiltration and factor distribution of adaptive immune using bioinformatics tools. T cells from activated rat were cultured on titanium nanotubes that were prepared by anodization with different diameters (P-0, NT15-30 nm, NT40-100 nm, NT70-200 nm).
Chem Biodivers
January 2025
Shaanxi University of Science and Technology, Chllege of Chemistry and Chemical Engineering, Weiyang Daxue Yuanqv, 710021, Xi'an, CHINA.
Bromodomain and extra terminal domain (BET) proteins play important roles in biological processes such as cell proliferation, differentiation, and signaling, and are involved in the occurrence and development of many diseases, including cancer and inflammatory diseases. Selective inhibitors targeting the first bromodomain (BD1) or the second bromodomain (BD2) have triggered a new wave of research to produce more specific and safer drugs. In this study, 37 novel selective BET BD2 inhibitors with anti-inflammatory activity are selected to construct robust Topomer CoMFA (q2=0.
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