Less than a decade ago, it was shown that bromodomains, acetyl lysine 'reader' modules found in proteins with varied functions, were highly tractable small-molecule targets. This is an unusual property for protein-protein or protein-peptide interaction domains, and it prompted a wave of chemical probe discovery to understand the biological potential of new agents that targeted bromodomains. The original examples, inhibitors of the bromodomain and extra-terminal (BET) class of bromodomains, showed enticing anti-inflammatory and anticancer activities, and several compounds have since advanced to human clinical trials. Here, we review the current state of BET inhibitor biology in relation to clinical development, and we discuss the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications. The lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bromodomains and other epigenetic readers.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s41573-019-0030-7 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition 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.
View Article and Find Full Text PDFDisruption of the FOXM1 Regulatory Region Inhibits Tumor Progression in Ovarian Cancer by CRISPR-Cas9.
Drug Dev Res
February 2025
Department of Gynecology and Obstetrics, Affiliated Hospital of Nantong University, Nantong, China.
Ovarian cancer is the seventh most common lethal tumor among women in the world. FOXM1 is a transcription factor implicated in the initiation and progression of ovarian cancer by regulating key oncogenic genes. The role of regulatory regions in regulating the expression of FOXM1 in ovarian cancer is not completely clarified.
View Article and Find Full Text PDFDesign, synthesis, and antitumor evaluation of triazolopyridine derivatives as novel inhibitors for BRD4.
Eur J Med Chem
January 2025
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address:
The bromodomain-containing protein 4 (BRD4) is an epigenetic regulatory 'reader' belonging to the bromodomain and extra-terminal domain (BET) family. Several studies have demonstrated that the high expression of BRD4 is closely related to the occurrence and development of various cancers, so BRD4 has become a promising target for cancer treatment. However, there are no drugs targeting BRD4 available on the market, the development of novel BRD4 inhibitors is of great significance.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!