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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
Summary
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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