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AT1, a small molecular degrader of BRD4 based on proteolysis targeting chimera technology alleviates renal fibrosis and inflammation in diabetic nephropathy.
Bioorg Chem
January 2025
School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China. Electronic address:
Both type 1 and type 2 diabetes can lead to diabetic nephropathy (DN), a serious microvascular complication. Bromodomain 4 (BRD4), a member of the BET protein family, has been linked to various diseases, including cancer, inflammation, and fibrosis, and may be involved in the development of diabetes and its complications. In this study, we first explored the role and mechanism of BRD4 in DN.
View Article and Find Full Text PDFDesign, Synthesis, and Biological Evaluation of Thieno[3,2-]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors.
J Med Chem
January 2025
College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China.
The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound () was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC) = 112 ± 8 nM] and BRD4-BD1 (IC = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells.
View Article and Find Full Text PDFInhibition of BRD4 attenuated IFNγ-induced apoptosis in colorectal cancer organoids.
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 PDFStructure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers.
J 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 PDFDesign and evaluation of novel selective BET BD2 inhibitors by combining QSAR, molecular docking and molecular dynamics simulation techniques.
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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