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Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development

Juncheng Chen1, Pan Tang1, Yuxi Wang1,2

  • 1State Key Laboratory of Biotherapy and Cancer Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.

Journal of Medicinal Chemistry
|March 24, 2022
PubMed

Insights

Selective bromodomain and extraterminal (BET) inhibitors offer improved tolerability and efficacy over pan-BET inhibitors for treating cancers and inflammatory diseases. This review details selective BET-BD1 and BET-BD2 inhibitors and strategies for their development.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Bromodomain and extraterminal (BET) proteins interact with acetylated histones, playing roles in cancer and other diseases.
  • Pan-BET inhibitors show clinical promise but often cause toxicity.
  • Selective BET inhibitors targeting BET-BD1 or BET-BD2 offer potential for reduced toxicity and comparable or improved therapeutic efficacy.

Purpose of the Study:

  • To review known selective BET-BD1 and BET-BD2 inhibitors.
  • To summarize methods for enhancing selectivity and potency of these inhibitors.
  • To discuss future strategies for targeting BET bromodomains.

Main Methods:

  • Literature review of selective BET inhibitor studies.
  • Analysis of structure-activity relationships for BET-BD1 and BET-BD2 inhibitors.
  • Discussion of medicinal chemistry strategies for inhibitor design.

Main Results:

  • Identification of various selective BET-BD1 and BET-BD2 inhibitors.
  • Elucidation of different interaction modes contributing to selectivity.
  • Demonstration of potential therapeutic advantages of selective inhibitors.

Conclusions:

  • Selective BET inhibitors represent a promising therapeutic strategy with reduced toxicity.
  • Targeting BET-BD1 or BET-BD2 offers opportunities for developing safer and more effective treatments.
  • Further research into selective BET inhibitors is crucial for advancing cancer and inflammatory disease therapies.

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