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BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications
Kenneth K W To1, Enming Xing2, Ross C Larue3
1School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Abstract:
The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists of four conserved members (Brd2, Brd3, Brd4, and Brdt) that regulate numerous cancer-related and immunity-associated genes. They are epigenetic readers of histone acetylation with broad specificity. BET proteins are linked to cancer progression due to their interaction with numerous cellular proteins including chromatin-modifying factors, transcription factors, and histone modification enzymes. The spectacular growth in the clinical development of small-molecule BET inhibitors underscores the interest and importance of this protein family as an anticancer target. Current approaches targeting BET proteins for cancer therapy rely on acetylation mimics to block the bromodomains from binding chromatin. However, bromodomain-targeted agents are suffering from dose-limiting toxicities because of their effects on other bromodomain-containing proteins. In this review, we provided an updated summary about the evolution of small-molecule BET inhibitors. The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed. The novel strategy of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins and its therapeutic significance will also be highlighted. Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting.
Insights
Small-molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins are crucial for cancer therapy. Novel strategies, including dual inhibitors and PROTACs, aim to improve efficacy and reduce toxicity, with ET domain targeting showing promise.
Area of Science:
- Epigenetics and Molecular Biology
- Cancer Therapeutics
- Drug Discovery
Background:
- Mammalian bromodomain and extra-terminal domain (BET) proteins (Brd2, Brd3, Brd4, Brdt) are epigenetic readers regulating cancer and immunity genes.
- BET proteins interact with various cellular factors, implicating them in cancer progression.
- Small-molecule BET inhibitors are extensively studied for cancer therapy, primarily targeting bromodomains.
Purpose of the Study:
- To provide an updated review of small-molecule BET inhibitor evolution and novel therapeutic strategies.
- To highlight emerging approaches like bivalent inhibitors, dual kinase-BET inhibitors, PROTACs, and Brd4-selective inhibitors.
- To discuss the therapeutic potential of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins.
Main Methods:
- Review of current literature on BET inhibitor development.
- Analysis of novel inhibitor designs including bivalent, dual-target, PROTAC, and selective inhibitors.
- Exploration of strategies targeting the ET domain of BET proteins.
Main Results:
- Significant advancements in small-molecule BET inhibitor design have been made.
- Novel strategies like dual inhibition, PROTACs, and ET domain targeting offer improved therapeutic potential.
- Combination therapies with BET inhibitors show favorable clinical outcomes.
Conclusions:
- BET inhibitors represent a promising class of anticancer agents.
- Further research into specific biomarkers is crucial for optimizing BET inhibitor efficacy and overcoming resistance.
- Targeting the ET domain presents a novel therapeutic avenue for cancer treatment.
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