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BET Isoform Selectivity through Diverse Linkers for Bivalent Inhibitors: GSK785, a BRD2/4-Selective Bivalent BET

Francesco Rianjongdee1, Stephen J Atkinson1, Paul Bamborough1

  • 1GSK, Stevenage, Hertfordshire SG1 2NY, U.K.

Journal of Medicinal Chemistry
|December 30, 2025
PubMed

Insights

Researchers developed novel bivalent inhibitors targeting Bromodomain and Extra Terminal (BET) proteins. They discovered GSK785, a molecule demonstrating selective inhibition of BRD2 and BRD4, while sparing BRD3, offering potential for improved cancer therapies.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Bromodomain and Extra Terminal (BET) protein inhibition is a key strategy for treating cancer and inflammatory diseases.
  • Developing isoform-selective inhibitors is crucial to understand individual BET protein functions and reduce side effects associated with pan-BET inhibitors.
  • Existing pan-BET inhibitors face tolerability limitations in clinical applications.

Purpose of the Study:

  • To design and synthesize novel bivalent inhibitors for achieving Bromodomain and Extra Terminal (BET) protein isoform selectivity.
  • To investigate the impact of constrained linker geometries on the selectivity profile of bivalent BET inhibitors.
  • To identify a specific inhibitor with a selective targeting profile among BET protein family members.

Main Methods:

  • Design and synthesis of bivalent molecules utilizing conformationally restricted diamines as linkers.
  • Utilizing two BET-binding warheads connected by diverse linker geometries.
  • Evaluation of inhibitor profiles across different BET protein isoforms.

Main Results:

  • The Bromodomain and Extra Terminal (BET) protein isoforms demonstrated high accommodation for bivalent molecules with varied linker designs.
  • Discovery of compound 9h (GSK785), a novel bivalent inhibitor.
  • GSK785 exhibits a unique BRD2/4-selective, BRD3-sparing inhibition profile.

Conclusions:

  • Bivalent inhibitors with constrained linkers represent a viable strategy for achieving Bromodomain and Extra Terminal (BET) protein isoform selectivity.
  • The identified inhibitor GSK785 offers a promising therapeutic candidate with a distinct selectivity profile for potential use in oncology and immuno-inflammatory diseases.
  • Further research into GSK785 could elucidate specific therapeutic applications and optimize its clinical potential.

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