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Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors
F Anthony Romero1, Alexander M Taylor2, Terry D Crawford1
1Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Abstract:
Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" that ultimately determine the functional outcome of the post-translational modification. Because the initial discovery of selective BET inhibitors have helped define the role of that protein family in oncology and inflammation, BET bromodomains have continued to garner the most attention of any other bromodomain. More recently, non-BET bromodomain inhibitors that are potent and selective have been disclosed for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B. Such novel inhibitors can be used to probe the physiological function of these non-BET bromodomains and further understanding of their role in certain disease states. Here, we provide an update to the progress in identifying selective bromodomain inhibitors and their use as biological tools, as well as our perspective on the field.
Insights
Selective inhibitors targeting bromodomains, epigenetic "readers" of histone modifications, are advancing research. Novel non-BET bromodomain inhibitors offer new tools to explore their roles in disease.
Area of Science:
- Biochemistry
- Epigenetics
- Chemical Biology
Background:
- Bromodomains are protein modules recognizing acetylated lysine on histones, crucial for epigenome regulation.
- BET bromodomains have been extensively studied due to their role in oncology and inflammation.
- Recent advances include potent and selective inhibitors for various non-BET bromodomains.
Purpose of the Study:
- To provide an update on the development of selective bromodomain inhibitors.
- To highlight the use of these inhibitors as biological tools.
- To discuss the role of non-BET bromodomains in disease states.
Main Methods:
- Identification and characterization of selective small molecule inhibitors.
- Application of inhibitors to probe physiological functions.
- Review of recent progress in the field.
Main Results:
- Disclosure of potent and selective inhibitors for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B.
- Demonstration of the utility of these inhibitors in biological studies.
- Advancement in understanding bromodomain function.
Conclusions:
- Selective bromodomain inhibitors are valuable tools for biological research.
- Targeting non-BET bromodomains offers new therapeutic avenues.
- Continued development of these inhibitors will deepen our understanding of epigenetics and disease.
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