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Recent Developments in Targeting Bromodomain and Extra Terminal Domain Proteins for Cancer Therapeutics

Maohua Cai1,2, Jinyun Dong1, Haobin Li1,2

  • 1The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou310022, China.

Current Medicinal Chemistry
|February 14, 2022
PubMed

Insights

Selective Bromodomain and extra-terminal domain (BET) inhibitors and Proteolysis Targeting Chimeras (PROTACs) are needed due to adverse events from pan BET inhibitors. This review focuses on BRD4-selective inhibitors and PROTAC degraders.

Area of Science:

  • Molecular Biology
  • Medicinal Chemistry
  • Oncology

Background:

  • Bromodomain and extra-terminal domain (BET) proteins are implicated in diseases like cancer and inflammation.
  • Existing pan BET inhibitors show efficacy but cause significant adverse events, limiting clinical use.
  • There is a critical need for developing targeted BET inhibitors and PROTACs.

Purpose of the Study:

  • To review the structure of BET proteins.
  • To summarize recent advancements in BET inhibitor development.
  • To focus on BRD4-selective inhibitors and PROTAC degraders.

Main Methods:

  • Literature review of BET protein structure and function.
  • Analysis of preclinical and clinical data on BET inhibitors.
  • Examination of novel therapeutic strategies, including selective inhibitors and PROTACs.

Main Results:

  • Pan BET inhibitors demonstrate preclinical efficacy but face clinical challenges due to toxicity.
  • BRD4-selective inhibitors offer a promising alternative with potentially improved safety profiles.
  • PROTACs targeting BET proteins represent an emerging therapeutic modality for targeted protein degradation.

Conclusions:

  • Targeted inhibition and degradation of BET proteins, particularly BRD4, are crucial for overcoming the limitations of current therapies.
  • Selective BET inhibitors and PROTACs hold significant potential for treating BET-associated malignancies and inflammatory diseases.
  • Further research into BRD4-selective agents and PROTACs is warranted to advance clinical applications.
Keywords:
BETBRD4CancerPROTACdrug designinhibitor

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