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Bromodomain Drug Discovery - the Past, the Present, and the Future

Mehrosh Pervaiz1, Pankaj Mishra1, Stefan Günther1

  • 1Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 9, 79104, Freiburg, Germany.

Chemical Record (New York, N.Y.)
|October 6, 2018
PubMed

Insights

Bromodomain (BRD) inhibitors show promise for cancer, but toxic side effects necessitate new strategies. Research explores combination therapies, dual inhibitors, PROTACs, and non-BET targets for improved therapeutic outcomes.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Bromodomains (BRDs) are epigenetic regulators and validated drug targets, particularly BRD4, with inhibitors like JQ1 driving anti-cancer drug development.
  • While BRD inhibitors have shown early success, clinical trials reveal significant toxic side effects and pending validation against existing therapies.

Purpose of the Study:

  • To review milestones in bromodomain drug discovery.
  • To evaluate novel strategies for overcoming challenges in BRD-targeted drug development.
  • To explore emerging applications of BRD inhibitors beyond oncology.

Main Methods:

  • Literature review of bromodomain inhibitor research.
  • Analysis of clinical trial data for BET-inhibitors.
  • Evaluation of emerging therapeutic strategies including combination therapies, dual inhibitors, and PROTACs.
  • Assessment of non-BET bromodomain targets and applications in parasitic diseases.

Main Results:

  • JQ1 and other BET inhibitors have initiated a successful drug discovery pathway for anti-cancer agents.
  • Clinical evaluations indicate potential toxicities associated with BET-inhibitor treatments.
  • New approaches like combination therapies, dual inhibitors, and PROTACs are being investigated to enhance efficacy and reduce side effects.
  • Bromodomains are emerging as potential therapeutic targets for diseases beyond cancer, such as malaria.

Conclusions:

  • Bromodomain and Extra-Terminal domain (BET) inhibitors represent a significant advancement in targeted cancer therapy, but clinical translation faces challenges due to side effects.
  • Innovative strategies including combination therapies, dual-target inhibitors, and proteolysis targeting chimeras (PROTACs) are crucial for optimizing BET inhibitor efficacy and safety.
  • The therapeutic potential of targeting bromodomains extends to infectious diseases, highlighting their broader significance in drug discovery.
Keywords:
BET-inhibitorsPROTACsbromodomainsdrug discoverydual target inhibitorsepigenetics

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