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Bromodomain inhibitors and cancer therapy: From structures to applications
Montserrat Pérez-Salvia1, Manel Esteller1,2,3
1a Cancer Epigenetics and Biology Program (PEBC) , Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona , Catalonia , Spain.
Abstract:
Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are "writers," "erasers," or "readers" of histone modification marks are common. Bromodomains are "readers" that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.
Insights
Cancer involves epigenetic changes, particularly in histone modification "readers" like bromodomains. Inhibitors targeting these bromodomain proteins offer a new strategy for developing anti-cancer agents.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- Epigenetic landscape aberrations are key features of cancer.
- Enzymes involved in histone modification, including "readers" like bromodomains, are frequently altered.
- Bromodomains bind acetylated lysines, regulating gene transcription and acting as epigenetic regulators.
Purpose of the Study:
- To review the structures and mechanisms of Bromodomain and Extra-Terminal motif (BET) and non-BET inhibitors.
- To discuss the current development status of these inhibitors.
- To highlight their potential as novel anti-cancer agents.
Main Methods:
- Review of existing literature on bromodomain inhibitors.
- Analysis of structural and mechanistic data for BET and non-BET inhibitors.
- Assessment of preclinical and clinical development data for anti-cancer applications.
Main Results:
- Bromodomain inhibitors have elucidated the biological functions of bromodomain-containing proteins.
- Small molecules targeting bromodomains represent a promising new therapeutic avenue for cancer.
- Both BET and non-BET inhibitors are under active investigation for their anti-cancer efficacy.
Conclusions:
- Targeting bromodomains is a viable strategy for cancer therapy.
- Further development of bromodomain inhibitors holds significant promise for oncology.
- Understanding bromodomain function is crucial for advancing epigenetic-based cancer treatments.
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